54 results on '"Yue Zou"'
Search Results
2. Ascorbic acid induced degradation of polysaccharide from natural products: a review
- Author
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Shaoping Nie, Ming-Yue Zou, Jun-Yi Yin, and Xie Mingyong
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Ascorbic Acid ,02 engineering and technology ,Polysaccharide ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Polysaccharide degradation ,Polysaccharides ,Structural Biology ,Dietary Carbohydrates ,Food science ,Molecular Biology ,Volume concentration ,030304 developmental biology ,chemistry.chemical_classification ,Biological Products ,0303 health sciences ,Hydrolysis ,Spectrum Analysis ,General Medicine ,021001 nanoscience & nanotechnology ,Ascorbic acid ,chemistry ,Fruits and vegetables ,Degradation (geology) ,Hydroxyl radical ,0210 nano-technology ,Oxidation-Reduction - Abstract
Polysaccharide derived from natural products has a wide range of sources and mild properties, and exhibit various bioactivities. Ascorbic acid is one of the most important nutrients in fruits and vegetables, as well as their products. Ascorbic acid and polysaccharide coexist in many systems during food production and processing. Many studies have found that ascorbic acid at low concentrations degrades polysaccharide derived from natural products via hydroxyl radical. In this paper, the research progress on ascorbic acid induced polysaccharide degradation is summarized from four aspects: mechanism of action, analytical methods, influencing factors and bioactivity of degradation products. It is expected to provide a theoretical basis for further research.
- Published
- 2020
3. ATR prevents Ca2+ overload‐induced necrotic cell death through phosphorylation‐mediated inactivation of PARP1 without DNA damage signaling
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Xiaochun Yu, Yue Zou, Yetunde Makinwa, Hui Wang-Heaton, Phillip R. Musich, Brian M. Cartwright, Nikolozi Shkriabai, Mamuka Kvaratskhelia, Zhengke Li, Benjamin Hilton, Qian Chen, and Shengheng Guan
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0301 basic medicine ,Programmed cell death ,DNA damage ,Poly (ADP-Ribose) Polymerase-1 ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Mitochondrion ,Biochemistry ,PARP1 ,necrosis ,03 medical and health sciences ,chemistry.chemical_compound ,Neuroblastoma ,0302 clinical medicine ,Genetics ,Tumor Cells, Cultured ,Humans ,Kinase activity ,Phosphorylation ,Molecular Biology ,Research Articles ,Kinase ,Chemistry ,Ca2+ overload ,PARP1 phosphorylation ,Cell biology ,Oxidative Stress ,030104 developmental biology ,ATR ,Ionomycin ,Calcium ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Biotechnology ,Research Article ,DNA Damage ,Signal Transduction - Abstract
Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid‐induced necrotic death of cells including SH‐SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site‐specific phosphorylation inactivates PARP1, inhibiting ionophore‐induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR‐mediated anti‐necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.
- Published
- 2021
4. Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients
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Shaoxin Shi, Jumei Liu, Jin Wang, Yuan Wu, Huabin Xie, Huiming Ye, Li Zhao, Shiwei He, Yue Zou, and Shengxiang Ge
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Stable dosage ,Bioinformatics analysis ,Bioinformatics ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Logistic regression ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Evidence Based Medicine ,Bioinformatic analysis ,microRNA ,medicine ,Genetics ,Molecular Biology ,business.industry ,General Neuroscience ,Warfarin dose ,lcsh:R ,Warfarin ,General Medicine ,Hematology ,Precision medicine ,Reverse transcription polymerase chain reaction ,MicroRNAs ,030220 oncology & carcinogenesis ,Pharmacogenomics ,General Agricultural and Biological Sciences ,business ,medicine.drug - Abstract
Background We used bioinformatic analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) assays to investigate the association between plasma microRNAs (miRNAs) and stable warfarin dosage in a Chinese Han population. Methods Bioinformatics analysis was used to screen out potential warfarin dose-associated miRNAs. Three plasma miRNAs were validated in 99 samples by RT-qPCR. Kruskal–Wallis test and multivariate logistic regression were used to compare differences in plasma miRNAs expression levels between three warfarin dosage groups. Results There were significant between-group differences among the three dose groups for hsa-miR-133b expression (p = 0.005), but we observed an “n-shaped” dose-dependent curve rather than a linear relationship. Expression levels of hsa-miR-24-3p (p = 0.475) and hsa-miR-1276 (p = 0.558) were not significantly different in the multivariate logistic regression. Conclusion miRNAs have received extensive attention as ideal biomarkers and possible therapeutic targets for various diseases. However, they are not yet widely used in precision medicine. Our results indicate that hsa-miR-133b may be a possible reference factor for the warfarin dosage algorithm. These findings emphasize the importance of a comprehensive evaluation of complex relationships in warfarin dose prediction models and provide new avenues for future pharmacogenomics studies.
- Published
- 2020
5. Dictyostelid Cellular Slime Molds from Christmas Island, Indian Ocean
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Yue Zou, Steven L. Stephenson, Yu Li, Xinru Li, Wenxiu Li, Pu Liu, and Songhao Che
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0106 biological sciences ,0301 basic medicine ,lcsh:QR1-502 ,Christmas Island ,Ecological and Evolutionary Science ,phylogeny ,010603 evolutionary biology ,01 natural sciences ,Microbiology ,lcsh:Microbiology ,Amoebozoa ,Soil ,taxonomy ,03 medical and health sciences ,Phylogenetics ,Cavenderia ,Dictyostelium ,Indian Ocean ,Molecular Biology ,Forest floor ,biology ,Ecology ,fungi ,Australia ,biology.organism_classification ,QR1-502 ,Dictyostelium purpureum ,Indian ocean ,030104 developmental biology ,Geography ,Taxonomy (biology) ,Dictyosteliida ,Research Article - Abstract
Reported here are the results of a study for dictyostelids carried out on Christmas Island, Indian Ocean. Six isolates representing four species of dictyostelid cellular slime molds were obtained from two of the four localities from which samples were collected on the island. Two of the species (Dictyostelium insulinativitatis and D. barbarae) belong to the Dictyosteliaceae, genus Dictyostelium, and are new to science. These are described based on both morphology and phylogeny. The diversity and abundance of dictyostelids on Christmas Island appear to be low, which might in part be due to the abundance of land crabs, which considerably reduce the extent of the litter layer on the forest floor., Christmas Island (10°30′S, 105°40′E) is an Australian external territory located in the Indian Ocean, approximately 350 km south of Java and Sumatra and about 1,550 km northwest of the closest point on the Australian mainland. In May 2017, 20 samples of soil/humus were collected on Christmas Island and processed for dictyostelid cellular slime molds. Four species were recovered. Two of these (Dictyostelium purpureum and Cavenderia aureostipes) are common and widely distributed throughout the world, but two other species (Dictyostelium insulinativitatis sp. nov. and Dictyostelium barbarae sp. nov.) were found to be new to science and are described here. IMPORTANCE Reported here are the results of a study for dictyostelids carried out on Christmas Island, Indian Ocean. Six isolates representing four species of dictyostelid cellular slime molds were obtained from two of the four localities from which samples were collected on the island. Two of the species (Dictyostelium insulinativitatis and D. barbarae) belong to the Dictyosteliaceae, genus Dictyostelium, and are new to science. These are described based on both morphology and phylogeny. The diversity and abundance of dictyostelids on Christmas Island appear to be low, which might in part be due to the abundance of land crabs, which considerably reduce the extent of the litter layer on the forest floor.
- Published
- 2019
6. Proteasome Inhibition Increases Interleukin‐8 Expression in Triple Negative Breast Cancer Cells, Resulting in Their Increased Survival, Proliferation, and Migration
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Yue Zou, Ivana Vancurova, Sveta Padmanabhan, Mohammad N. Uddin, and Bijaya Gaire
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Proteasome Inhibition ,Chemistry ,Genetics ,Cancer research ,Interleukin 8 ,Molecular Biology ,Biochemistry ,Triple-negative breast cancer ,Biotechnology - Published
- 2019
7. A novel thyroid hormone receptor isoform, TRβ2-46, promotes SKP2 expression and retinoblastoma cell proliferation
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Donglai Qi, David Cobrinik, Hardeep Singh, Yue Zou, Zhengke Li, and Binghui Shen
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0301 basic medicine ,Gene isoform ,Cell ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Isoforms ,Molecular Biology ,S-Phase Kinase-Associated Proteins ,Cell Proliferation ,Gene knockdown ,Thyroid hormone receptor ,030102 biochemistry & molecular biology ,Chemistry ,Cell growth ,Retinoblastoma ,Protein Stability ,Thyroid Hormone Receptors beta ,Cell Biology ,Cell cycle ,medicine.disease ,Cell biology ,Neoplasm Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Accelerated Communications ,Gene Knockdown Techniques ,Carcinogenesis - Abstract
Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating RB1 mutations and loss of functional RB protein. The cone precursor's response to RB loss involves cell type-specific signaling circuitry that helps to drive tumorigenesis. One component of the cone precursor circuitry, the thyroid hormone receptor β2 (TRβ2), enables the aberrant proliferation of diverse RB-deficient cells in part by opposing the down-regulation of S-phase kinase-associated protein 2 (SKP2) by the more widely expressed and tumor-suppressive TRβ1. However, it is unclear how TRβ2 opposes TRβ1 to enable SKP2 expression and cell proliferation. Here, we show that in human retinoblastoma cells TRβ2 mRNA encodes two TRβ2 protein isoforms: a predominantly cytoplasmic 54-kDa protein (TRβ2-54) corresponding to the well-characterized full-length murine Trβ2 and an N-terminally truncated and exclusively cytoplasmic 46-kDa protein (TRβ2-46) that starts at Met-79. Whereas TRβ2 knockdown decreased SKP2 expression and impaired retinoblastoma cell cycle progression, re-expression of TRβ2-46 but not TRβ2-54 stabilized SKP2 and restored proliferation to an extent similar to that of ectopic SKP2 restoration. We conclude that TRβ2-46 is an oncogenic thyroid hormone receptor isoform that promotes SKP2 expression and SKP2-dependent retinoblastoma cell proliferation.
- Published
- 2019
8. The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells
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Yan Zhu, Ales Vancura, Yue Zou, Sveta Padmanabhan, Pengli Bu, Mohammad M. Uddin, and Ivana Vancurova
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0301 basic medicine ,Transcription, Genetic ,Apoptosis ,Biochemistry ,Proto-Oncogene Mas ,B7-H1 Antigen ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Interferon ,B-Cell Lymphoma 3 Protein ,PD-L1 ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Transcriptional regulation ,Humans ,Gene Regulation ,Neutralizing antibody ,Promoter Regions, Genetic ,Molecular Biology ,Cell Proliferation ,biology ,Oncogene ,Chemistry ,Ovary ,Transcription Factor RelA ,Epithelial Cells ,Cell Biology ,Cell Cycle Checkpoints ,medicine.disease ,Antibodies, Neutralizing ,Immune checkpoint ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Female ,Tumor Escape ,Ovarian cancer ,E1A-Associated p300 Protein ,medicine.drug ,Signal Transduction ,Transcription Factors - Abstract
The proto-oncogene Bcl3 induces survival and proliferation in cancer cells; however, its function and regulation in ovarian cancer (OC) remain unknown. Here, we show that Bcl3 expression is increased in human OC tissues. Surprisingly, however, we found that in addition to promoting survival, proliferation, and migration of OC cells, Bcl3 promotes both constitutive and interferon-γ (IFN)-induced expression of the immune checkpoint molecule PD-L1. The Bcl3 expression in OC cells is further increased by IFN, resulting in increased PD-L1 transcription. The mechanism consists of an IFN-induced, Bcl3- and p300-dependent PD-L1 promoter occupancy by Lys-314/315 acetylated p65 NF-κB. Blocking PD-L1 by neutralizing antibody reduces proliferation of OC cells overexpressing Bcl3, suggesting that the pro-proliferative effect of Bcl3 in OC cells is partly mediated by PD-L1. Together, this work identifies PD-L1 as a novel target of Bcl3, and links Bcl3 to IFNγ signaling and PD-L1-mediated immune escape.
- Published
- 2018
9. Reprint of: XPA is primarily cytoplasmic but is transported into the nucleus upon UV damage in a cell cycle dependent manner
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Phillip R. Musich, Zhengke Li, Steven M. Shell, and Yue Zou
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Cell Nucleus ,endocrine system ,Cytoplasm ,Cell Cycle ,Humans ,Cell Biology ,Molecular Biology ,Biochemistry ,Article ,Cell Line ,Xeroderma Pigmentosum Group A Protein - Abstract
Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined. We analyzed the human transcriptome by RNA sequencing (RNA-Seq). We first confirmed that XPA is confined to the cell nucleus even in the absence of external DNA damage, in contrast to previous reports that XPA is normally resident in the cytoplasm and is imported following DNA damage. We then analyzed four genetically matched human cell line pairs deficient or proficient in XPA. Of the ∼14,000 genes transcribed in each cell line, 325 genes (2%) had a significant XPA-dependent directional change in gene expression that was common to all four pairs (with a false discovery rate of 0.05). These genes were enriched in pathways for the maintenance of mitochondria. Only 27 common genes were different by more than 1.5-fold. The most significant hits were AKR1C1 and AKR1C2, involved in steroid hormone metabolism. AKR1C2 protein was lower in all of the immortalized XPA-deficient cells. Retinoic acid treatment led to modest XPA-dependent activation of some genes with transcription-related functions. We conclude that XPA status does not globally influence human gene transcription. However, XPA significantly influences expression of a small subset of genes important for mitochondrial functions and steroid hormone metabolism. The results may help explain defects in neurological function and sterility in individuals with xeroderma pigmentosum.
- Published
- 2017
10. XPA is primarily cytoplasmic but is transported into the nucleus upon UV damage in a cell cycle dependent manner
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Zhengke Li, Steven M. Shell, Phillip R. Musich, and Yue Zou
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0301 basic medicine ,Cell Nucleus ,Cytoplasm ,Dependent manner ,DNA Repair ,Ultraviolet Rays ,Cell Cycle ,Cell Biology ,Cell cycle ,Biology ,Biochemistry ,Cell biology ,Xeroderma Pigmentosum Group A Protein ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cell cycle genetics ,medicine ,Humans ,Molecular Biology ,Nucleus ,DNA Damage - Published
- 2017
11. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes
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Brian M. Cartwright, Hui Tang, Ji Liu, Antonio E. Rusiñol, Benjamin Hilton, Phillip R. Musich, Youjie Wang, Rowdy Jones, Yiyong Liu, Yue Zou, and Maya Breitman
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0301 basic medicine ,Genome instability ,endocrine system ,DNA Repair ,DNA damage ,DNA repair ,Apoptosis ,Biochemistry ,Progeroid syndromes ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Progeria ,Proliferating Cell Nuclear Antigen ,Genetics ,medicine ,Humans ,DNA Breaks, Double-Stranded ,RNA, Small Interfering ,Molecular Biology ,Cells, Cultured ,biology ,integumentary system ,Point mutation ,Research ,Fibroblasts ,Progerin ,medicine.disease ,Lamin Type A ,Proliferating cell nuclear antigen ,Cell biology ,Xeroderma Pigmentosum Group A Protein ,Protein Subunits ,Protein Transport ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Biotechnology - Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene, resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds-ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, suggesting that XPA-replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin-induced genome instability and accelerated replicative senescence in HGPS.-Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., Zou, Y. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.
- Published
- 2017
12. RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage
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Erin M. Wolf Horrell, Mary C. Boulanger, Stuart G. Jarrett, John A. D'Orazio, Jillian C. Vanover, Yue Zou, and Perry A. Christian
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congenital, hereditary, and neonatal diseases and abnormalities ,Xeroderma pigmentosum ,DNA damage ,DNA repair ,Mutagenesis ,Cell Biology ,Biology ,medicine.disease ,Molecular biology ,Ataxia Telangiectasia Mutated Proteins ,medicine ,Signal transduction ,Protein kinase A ,Molecular Biology ,Nucleotide excision repair - Abstract
The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.
- Published
- 2014
13. Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells
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Ales Vancura, Bipradeb Singha, Yue Zou, Ivana Vancurova, Mohammad M. Uddin, Pengli Bu, and Himavanth R. Gatla
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0301 basic medicine ,musculoskeletal diseases ,endocrine system diseases ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,IκB kinase ,Biology ,Hydroxamic Acids ,Biochemistry ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,medicine ,Animals ,Humans ,Interleukin 8 ,Viability assay ,Promoter Regions, Genetic ,Molecular Biology ,Vorinostat ,Ovarian Neoplasms ,Interleukin-8 ,Ovary ,Acetylation ,Molecular Bases of Disease ,Cell Biology ,medicine.disease ,Molecular biology ,I-kappa B Kinase ,Up-Regulation ,Histone Deacetylase Inhibitors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Histone deacetylase ,Ovarian cancer ,medicine.drug - Abstract
Overexpression of the pro-angiogenic chemokine IL-8 (CXCL8) is associated with a poor prognosis in several solid tumors, including epithelial ovarian cancer (EOC). Even though histone deacetylase (HDAC) inhibition has shown remarkable antitumor activity in hematological malignancies, it has been less effective in solid tumors, including EOC. Here we report results that may explain the decreased efficiency of HDAC inhibition in EOC, based on our data demonstrating that HDAC inhibition specifically induces expression of IL-8/CXCL8 in SKOV3, CAOV3, and OVCAR3 cells. Suppression or neutralization of vorinostat-induced IL-8/CXCL8 potentiates the vorinostat inhibitory effect on cell viability and proliferation. The IL-8/CXCL8 expression induced by vorinostat in EOC cells is dependent on IκB kinase (IKK) activity and associated with a gene-specific recruitment of IKKβ and IKK-dependent recruitment of p65 NFκB to the IL-8/CXCL8 promoter. In addition, HDAC inhibition induces acetylation of p65 and histone H3 and their IL-8/CXCL8 promoter occupancy. In vivo results demonstrate that combining vorinostat and the IKK inhibitor Bay 117085 significantly reduces tumor growth in nude mice compared with control untreated mice or either drug alone. Mice in the combination group had the lowest IL-8/CXCL8 tumor levels and the lowest tumor expression of the murine neutrophil [7/4] antigen, indicating reduced neutrophil infiltration. Together, our results demonstrate that HDAC inhibition specifically induces IL-8/CXCL8 expression in EOC cells and that the mechanism involves IKK, suggesting that using IKK inhibitors may increase the effectiveness of HDAC inhibitors when treating ovarian cancer and other solid tumors characterized by increased IL-8/CXCL8 expression.
- Published
- 2016
14. FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1
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Yue Zou, Jing-Yuan Liu, Zizheng Dong, Chao J. Wang, Valerie E. Fako, Xi Wu, Lincoln James Barlow, Jian Ting Zhang, and Moises A. Serrano
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0301 basic medicine ,Multidisciplinary ,biology ,DNA repair ,Poly ADP ribose polymerase ,Lipid metabolism ,NF-κB ,Molecular biology ,Ku Protein ,Cell biology ,03 medical and health sciences ,Fatty acid synthase ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,PNAS Plus ,Cancer cell ,biology.protein ,Transcriptional regulation - Abstract
Fatty acid synthase (FASN), the sole cytosolic mammalian enzyme for de novo lipid synthesis, is crucial for cancer cell survival and associates with poor prognosis. FASN overexpression has been found to cause resistance to genotoxic insults. Here we tested the hypothesis that FASN regulates DNA repair to facilitate survival against genotoxic insults and found that FASN suppresses NF-κB but increases specificity protein 1 (SP1) expression. NF-κB and SP1 bind to a composite element in the poly(ADP-ribose) polymerase 1 (PARP-1) promoter in a mutually exclusive manner and regulate PARP-1 expression. Up-regulation of PARP-1 by FASN in turn increases Ku protein recruitment and DNA repair. Furthermore, lipid deprivation suppresses SP1 expression, which is able to be rescued by palmitate supplementation. However, lipid deprivation or palmitate supplementation has no effect on NF-κB expression. Thus, FASN may regulate NF-κB and SP1 expression using different mechanisms. Altogether, we conclude that FASN regulates cellular response against genotoxic insults by up-regulating PARP-1 and DNA repair via NF-κB and SP1.
- Published
- 2016
15. Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA bending/distortion as a primary recognition factor
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Fengting Liang, Yue Zou, Satyakam Patnaik, Alexander D. MacKerell, Benjamin Hilton, Bin Lin, Eva Darian, Bongsup P. Cho, and Vipin Jain
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Models, Molecular ,DNA Repair ,DNA repair ,DNA damage ,Electrophoretic Mobility Shift Assay ,Context (language use) ,Molecular Dynamics Simulation ,Genome Integrity, Repair and Replication ,Biology ,010402 general chemistry ,01 natural sciences ,DNA Adducts ,03 medical and health sciences ,chemistry.chemical_compound ,Escherichia coli ,Genetics ,Aminobiphenyl Compounds ,Electrophoretic mobility shift assay ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,Fluorenes ,0303 health sciences ,Endodeoxyribonucleases ,Base Sequence ,Transition (genetics) ,Circular Dichroism ,Escherichia coli Proteins ,Deoxyguanosine ,2-Acetylaminofluorene ,Molecular biology ,0104 chemical sciences ,chemistry ,Biochemistry ,Nucleic Acid Conformation ,Thermodynamics ,DNA ,DNA Damage ,Nucleotide excision repair - Abstract
The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*CN- sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of ‘stacked’ (S) and ‘B-type’ (B) conformers, whereas the N-acetylated FAAF also samples a ‘wedge’ (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A- to -T polarity swap in the G*CA/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2- to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli. These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3′-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli.
- Published
- 2012
16. ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1
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Xiao Zhen Zhou, Brian M. Cartwright, Kun Ping Lu, Hui Wang, Moises A. Serrano, Phillip R. Musich, Benjamin Hilton, Yue Zou, and Zhengke Li
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Protein Conformation ,DNA damage ,Cell ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Mitochondrion ,Article ,03 medical and health sciences ,0302 clinical medicine ,Bcl-2-associated X protein ,stomatognathic system ,Cell Line, Tumor ,medicine ,Prolyl isomerase ,Humans ,Kinase activity ,Protein kinase A ,Molecular Biology ,030304 developmental biology ,bcl-2-Associated X Protein ,Peptidylprolyl isomerase ,0303 health sciences ,Binding Sites ,biology ,Kinase ,Cytochromes c ,Cell Biology ,Peptidylprolyl Isomerase ,HCT116 Cells ,Cell biology ,Mitochondria ,NIMA-Interacting Peptidylprolyl Isomerase ,medicine.anatomical_structure ,HEK293 Cells ,Gene Expression Regulation ,Biochemistry ,030220 oncology & carcinogenesis ,biology.protein ,PIN1 ,biological phenomena, cell phenomena, and immunity ,DNA Damage ,BH3 Interacting Domain Death Agonist Protein - Abstract
ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented, but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.
- Published
- 2016
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17. DNA-PK, ATM and ATR collaboratively regulate p53–RPA interaction to facilitate homologous recombination DNA repair
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Steve M. Patrick, Mohan Dangeti, Phillip R. Musich, Moises A. Serrano, Brian M. Cartwright, Yue Zou, Marina Roginskaya, and Zhengke Li
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Cancer Research ,DNA damage ,Protein subunit ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,DNA-Activated Protein Kinase ,Protein Serine-Threonine Kinases ,Biology ,Transfection ,complex mixtures ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Replication Protein A ,Genetics ,Humans ,Phosphorylation ,Molecular Biology ,Replication protein A ,030304 developmental biology ,0303 health sciences ,Tumor Suppressor Proteins ,Recombinational DNA Repair ,Genes, p53 ,Molecular biology ,DNA-Binding Proteins ,Non-homologous end joining ,enzymes and coenzymes (carbohydrates) ,chemistry ,030220 oncology & carcinogenesis ,Tumor Suppressor Protein p53 ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,Ataxia telangiectasia and Rad3 related ,DNA ,DNA Damage - Abstract
Homologous recombination (HR) and nonhomologous end joining (NHEJ) are two distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-dependent protein kinase (DNA-PK), the core component of NHEJ, partnering with DNA-damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), regulates HR repair of DSBs. The regulation was accomplished through modulation of the p53 and replication protein A (RPA) interaction. We show that upon DNA damage, p53 and RPA were freed from a p53-RPA complex by simultaneous phosphorylations of RPA at the N-terminus of RPA32 subunit by DNA-PK and of p53 at Ser37 and Ser46 in a Chk1/Chk2-independent manner by ATR and ATM, respectively. Neither the phosphorylation of RPA nor of p53 alone could dissociate p53 and RPA. Furthermore, disruption of the release significantly compromised HR repair of DSBs. Our results reveal a mechanism for the crosstalk between HR repair and NHEJ through the co-regulation of p53-RPA interaction by DNA-PK, ATM and ATR.
- Published
- 2012
18. Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes
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Fang Xiao, Yue Zou, Yanhong Li, Caigao Zhong, Yuan Yang, Yuanyuan Deng, Peng Li, and Lu Dai
- Subjects
Chromium ,Cell Survival ,Caspase 3 ,Superoxide dismutase ,chemistry.chemical_compound ,Genetics ,Mitochondrial respiratory chain complex I ,Hexavalent chromium ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,Electron Transport Complex I ,Dose-Response Relationship, Drug ,biology ,General Medicine ,Molecular biology ,Mitochondria ,Enzyme Activation ,Mitochondrial respiratory chain ,chemistry ,Catalase ,Hepatocytes ,biology.protein ,Thioredoxin ,Reactive Oxygen Species - Abstract
Hexavalent chromium [Cr(VI)], which is used for various industrial applications, such as leather tanning and chroming, can cause a number of human diseases including inflammation and cancer. Cr(VI) exposure leads to severe damage to the liver, but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear. The present study provides evidence that Cr(VI) enhances reactive oxygen species (ROS) accumulation by inhibiting the mitochondrial respiratory chain complex (MRCC) I. Cr(VI) did not affect the expression levels of antioxidative proteins such as superoxide dismutase (SOD), catalase and thioredoxin (Trx), indicating that the antioxidative system was not involved in Cr(VI)-induced ROS accumulation. We found that ROS mediated caspase-3 activation partially depends on the downregulation of the heat shock protein (HSP) 70 and 90. In order to confirm our hypothesis that ROS plays a key role in Cr(VI)-mediated cytotoxicity, we used N-acetylcysteine (NAC) to inhibit the accumulation of ROS. NAC successfully blocked the inhibition of HSP70 and HSP90 as well as the activation of caspase-3, suggesting that ROS is essential in Cr(VI)-induced caspase-3 activation. By applying different MRCC substrates as electron donors, we also confirmed that Cr(VI) could accept the electrons leaked from MRCC I and the reduction occurs at MRCC I. In conclusion, the present study demonstrates that Cr(VI) induces ROS-dependent caspase-3 activation by inhibiting MRCC I activity, and MRCC I has been identified as a new target and a new mechanism for the apoptosis-inducing activity displayed by Cr(VI).
- Published
- 2012
19. Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy
- Author
-
Mohammad M. Uddin, Ivana Vancurova, Yue Zou, Himavanth R. Gatla, and Tamanna Sharma
- Subjects
lcsh:Medicine ,Artificial Gene Amplification and Extension ,Triple Negative Breast Neoplasms ,IκB kinase ,Biochemistry ,Polymerase Chain Reaction ,Receptors, Interleukin-8B ,Receptors, Interleukin-8A ,Bortezomib ,chemistry.chemical_compound ,0302 clinical medicine ,Breast Tumors ,Medicine and Health Sciences ,Cytotoxic T cell ,Small interfering RNAs ,CXC chemokine receptors ,lcsh:Science ,Triple-negative breast cancer ,Multidisciplinary ,Cell Death ,Transcriptional Control ,I-kappa B Kinase ,3. Good health ,Nucleic acids ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Drug Therapy, Combination ,Oligopeptides ,Proteasome Inhibitors ,Research Article ,medicine.drug ,Cell Nucleus Shape ,Proteasome Endopeptidase Complex ,Antineoplastic Agents ,Transfection ,Research and Analysis Methods ,03 medical and health sciences ,Cell Line, Tumor ,Breast Cancer ,Genetics ,medicine ,Humans ,Interleukin 8 ,Non-coding RNA ,Molecular Biology Techniques ,Molecular Biology ,Interleukin-8 ,lcsh:R ,Transcription Factor RelA ,Biology and Life Sciences ,Proteins ,Protein Complexes ,Proteasomes ,Cancers and Neoplasms ,Reverse Transcriptase-Polymerase Chain Reaction ,Carfilzomib ,Gene regulation ,chemistry ,Proteasome ,Cancer research ,RNA ,lcsh:Q ,Gene expression ,030215 immunology - Abstract
Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.
- Published
- 2018
20. Checkpoint Kinase ATR Promotes Nucleotide Excision Repair of UV-induced DNA Damage via Physical Interaction with Xeroderma Pigmentosum Group A
- Author
-
Yue Zou, Mamuka Kvaratskhelia, Nikolozi Shkriabai, Zhengke Li, Moises A. Serrano, Chris A. Brosey, Steven M. Shell, Phillip R. Musich, and Walter J. Chazin
- Subjects
endocrine system ,Cell cycle checkpoint ,Xeroderma pigmentosum ,DNA Repair ,Cell Survival ,Ultraviolet Rays ,DNA damage ,DNA repair ,Amino Acid Motifs ,Active Transport, Cell Nucleus ,Cell Cycle Proteins ,Pyrimidine dimer ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Mass Spectrometry ,Cell Line ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Point Mutation ,Phosphorylation ,Molecular Biology ,Cell Nucleus ,Point mutation ,Cell Biology ,medicine.disease ,Xeroderma Pigmentosum Group A Protein ,Cell biology ,chemistry ,DNA: Replication, Repair, Recombination, and Chromosome Dynamics ,Cancer research ,DNA ,DNA Damage ,Protein Binding ,Nucleotide excision repair - Abstract
In response to DNA damage, eukaryotic cells activate a series of DNA damage-dependent pathways that serve to arrest cell cycle progression and remove DNA damage. Coordination of cell cycle arrest and damage repair is critical for maintenance of genomic stability. However, this process is still poorly understood. Nucleotide excision repair (NER) and the ATR-dependent cell cycle checkpoint are the major pathways responsible for repair of UV-induced DNA damage. Here we show that ATR physically interacts with the NER factor Xeroderma pigmentosum group A (XPA). Using a mass spectrometry-based protein footprinting method, we found that ATR interacts with a helix-turn-helix motif in the minimal DNA-binding domain of XPA where an ATR phosphorylation site (serine 196) is located. XPA-deficient cells complemented with XPA containing a point mutation of S196A displayed a reduced repair efficiency of cyclobutane pyrimidine dimers as compared with cells complemented with wild-type XPA, although no effect was observed for repair of (6-4) photoproducts. This suggests that the ATR-dependent phosphorylation of XPA may promote NER repair of persistent DNA damage. In addition, a K188A point mutation of XPA that disrupts the ATR-XPA interaction inhibits the nuclear import of XPA after UV irradiation and, thus, significantly reduced DNA repair efficiency. By contrast, the S196A mutation has no effect on XPA nuclear translocation. Taken together, our results suggest that the ATR-XPA interaction mediated by the helix-turn-helix motif of XPA plays an important role in DNA-damage responses to promote cell survival and genomic stability after UV irradiation.
- Published
- 2009
21. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A
- Author
-
Phillip R. Musich and Yue Zou
- Subjects
Genome instability ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Xeroderma pigmentosum ,DNA Repair ,DNA repair ,DNA damage ,XPA ,Review ,Biology ,Genomic Instability ,03 medical and health sciences ,Progeria ,0302 clinical medicine ,medicine ,Animals ,Humans ,Protein Precursors ,030304 developmental biology ,0303 health sciences ,integumentary system ,premature aging ,Nuclear Proteins ,nutritional and metabolic diseases ,DNA double strand breaks ,Cell Biology ,Lamin Type A ,medicine.disease ,Progerin ,Molecular biology ,Hutchinson-Gilford progeria syndrome ,030220 oncology & carcinogenesis ,Lamin A ,DNA damage responses ,Lamin ,Nucleotide excision repair - Abstract
Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for a LMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.
- Published
- 2009
22. New Insights into the Roles of XPA and RPA in DNA Repair and Damage Responses
- Author
-
Yiyong Liu and Yue Zou
- Subjects
DNA repair ,Biochemistry (medical) ,Clinical Biochemistry ,Biology ,Molecular Biology ,Biochemistry ,Nucleotide excision repair ,Cell biology - Published
- 2007
23. Specific and Efficient Binding of Xeroderma Pigmentosum Complementation Group A to Double-Strand/Single-Strand DNA Junctions with 3‘- and/or 5‘-ssDNA Branches
- Author
-
Thomas M. Harris, Constance M. Harris, Yiyong Liu, Laureen C. Colis, Yue Zou, Steven M. Shell, Ashis K. Basu, Zhengguan Yang, Phillip R. Musich, and Marina Roginskaya
- Subjects
endocrine system ,Xeroderma pigmentosum ,DNA Repair ,DNA repair ,DNA damage ,Molecular Sequence Data ,DNA, Single-Stranded ,Plasma protein binding ,Spodoptera ,Biology ,Biochemistry ,DNA-binding protein ,Article ,Cell Line ,DNA Adducts ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Replication protein A ,Base Sequence ,medicine.disease ,Molecular biology ,humanities ,Xeroderma Pigmentosum Group A Protein ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,chemistry ,Nucleic Acid Conformation ,Baculoviridae ,DNA ,DNA Damage ,Protein Binding ,Nucleotide excision repair - Abstract
Human XPA is an important DNA damage recognition protein in nucleotide excision repair (NER). We previously observed that XPA binds to the DNA lesion as a homodimer [Liu, Y., Liu, Y., Yang, Z., Utzat, C., Wang, G., Basu, A. K., and Zou, Y. (2005) Biochemistry 44, 7361-7368]. Herein we report that XPA recognized undamaged DNA double-strand/single-strand (ds-ssDNA) junctions containing ssDNA branches with binding affinity (Kd = 49.1 +/- 5.1 nM) much higher than its ability to bind to DNA damage. The recognized DNA junction structures include the Y-shape junction (with both 3'- and 5'-ssDNA branches), 3'-overhang junction (with a 3'-ssDNA branch), and 5'-overhang junction (with a 5'-ssDNA branch). Using gel filtration chromatography and gel mobility shift assays, we showed that the highly efficient binding appeared to be carried out by the XPA monomer and that the binding was largely independent of RPA. Furthermore, XPA efficiently bound to six-nucleotide mismatched DNA bubble substrates with or without DNA adducts including C8 guanine adducts of AF, AAF, and AP and the T[6,4]T photoproducts. Using a set of defined DNA substrates with varying degrees of DNA bending, we also found that the XPC-HR23B complex recognized DNA bending, whereas neither XPA nor the XPA-RPA complex could bind to bent DNA. We propose that, besides DNA damage recognition, XPA may also play a novel role in stabilizing, via its high affinity to ds-ssDNA junctions, the DNA strand opening surrounding the lesion for stable formation of preincision NER intermediates. Our results provide a plausible mechanistic interpretation for the indispensable requirement of XPA for both global genome and transcription-coupled repairs. Since ds-ssDNA junctions are common intermediates in many DNA metabolic pathways, the additional potential role of XPA in cellular processes is discussed.
- Published
- 2006
24. DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A
- Author
-
Youjie Wang, Michael S. Sinensky, Antonio E. Rusiñol, Yue Zou, and Yiyong Liu
- Subjects
DNA Replication ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA damage ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Biology ,Article ,Progeroid syndromes ,Progeria ,medicine ,Farnesyltranstransferase ,Humans ,DNA Breaks, Double-Stranded ,Enzyme Inhibitors ,Protein Precursors ,Cell Nucleus ,integumentary system ,Tumor Suppressor Proteins ,DNA replication ,Nuclear Proteins ,nutritional and metabolic diseases ,Cell Biology ,Fibroblasts ,Lamin Type A ,Progerin ,medicine.disease ,Molecular biology ,Cell biology ,DNA-Binding Proteins ,Skin Abnormalities ,Restrictive dermopathy ,Lamin - Abstract
The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturation pathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated because of the compromise in genomic integrity. Inactivation of checkpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in these patient cells can partially overcome their early replication arrest. Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei. This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question the possibility of treatment of HGPS with FTIs alone.
- Published
- 2006
25. Recognition and Incision of Oxidative Intrastrand Cross-Link Lesions by UvrABC Nuclease
- Author
-
Qibin Zhang, Yue Zou, Yinsheng Wang, Yuesong Wang, Chunang Gu, and Zhengguan Yang
- Subjects
Pyrimidine ,Molecular Sequence Data ,Pyrimidine dimer ,medicine.disease_cause ,Biochemistry ,Article ,Substrate Specificity ,chemistry.chemical_compound ,Escherichia coli ,medicine ,Pyrimidone ,Endodeoxyribonucleases ,Base Sequence ,Molecular Structure ,biology ,Escherichia coli Proteins ,DNA ,Molecular biology ,chemistry ,Pyrimidine Dimers ,Duplex (building) ,biology.protein ,Nucleic Acid Conformation ,Oxidation-Reduction ,Nucleotide excision repair - Abstract
Nucleotide excision repair (NER) is a repair pathway that removes a variety of bulky DNA lesions in both prokaryotic and eukaryotic cells. The perturbation of DNA helix structure caused by the oxidative intrastrand lesions could render them good substrates for the NER pathway. Here we employed Escherichia coli (E. coli) NER enzymes, i.e., UvrA, UvrB and UvrC, to examine the incision efficiency of duplex DNA carrying three different oxidative intrastrand cross-link lesions, that is, G[8-5]C, G[8-5m]mC, and G[8-5m]T, and two dithymine photoproducts, namely, the cis,syn-cyclobutane pyrimidine dimer (T[c,s]T) and pyrimidine(6-4)pyrimidone product (T[6-4]T). Our results showed that T[6-4]T was the best substrate for UvrA binding, followed by G[8-5]C, G [8-5m]mC and G[8-5m]T, and then by T[c,s]T. The efficiencies of the UvrABC incisions of these lesions were consistent with their UvrA binding affinities: The stronger the binding to UvrA, the higher the incision rate. In addition, flanking DNA sequences appeared to have little effect on the binding affinity of UvrA toward G[8-5]C as AG[8-5]CA was only slightly preferred over CG[8-5] CG. Consistently, these two sequences exhibited almost no difference in incision rates. Furthermore, we investigated the thermal stability of dodecameric duplexes containing a G[8-5m]mC or G[8-5m] T and our results revealed that these two lesions destabilized the duplex, due to an increase in free energy for duplex formation at 37°C, by approximately 5.4 kcal/mol and 3.6 kcal/mol, respectively. The destabilizations to DNA helix caused by those lesions, for the most part, are correlated with the binding affinities of UvrA and incision rates of UvrABC. Taken together, the results from this study suggest that oxidative intrastrand lesions might be substrates for NER enzymes in vivo.
- Published
- 2006
26. ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation
- Author
-
Yiyong Liu, Xiaoming Wu, Steven M. Shell, and Yue Zou
- Subjects
DNA Replication ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Lung Neoplasms ,Cell cycle checkpoint ,Xeroderma pigmentosum ,DNA Repair ,Ultraviolet Rays ,DNA repair ,DNA damage ,Active Transport, Cell Nucleus ,Fluorescent Antibody Technique ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Adenocarcinoma ,Protein Serine-Threonine Kinases ,Biology ,Transfection ,Article ,Ataxia Telangiectasia ,Genetics ,medicine ,Humans ,RNA, Small Interfering ,Molecular Biology ,Cell Nucleus ,Tumor Suppressor Proteins ,Fibroblasts ,Cell cycle ,medicine.disease ,Xeroderma Pigmentosum Group A Protein ,Cell biology ,DNA-Binding Proteins ,Cell nucleus ,medicine.anatomical_structure ,Cancer research ,DNA Damage ,Nucleotide excision repair - Abstract
In response to DNA damage, mammalian cells activate various DNA repair pathways to remove DNA lesions and, meanwhile, halt cell cycle progressions to allow sufficient time for repair. The nucleotide excision repair (NER) and the ATR-dependent cell cycle checkpoint activation are two major cellular responses to DNA damage induced by UV irradiation. However, how these two processes are coordinated in the response is poorly understood. Here we showed that the essential NER factor XPA (xeroderma pigmentosum group A) underwent nuclear accumulation upon UV irradiation, and strikingly, such an event occurred in an ATR (Ataxia-Telangiectasia mutated and RAD3-related)-dependent manner. Either treatment of cells with ATR kinase inhibitors or transfection of cells with small interfering RNA targeting ATR compromised the UV-induced XPA nuclear translocation. Consistently, the ATR-deficient cells displayed no substantial XPA nuclear translocation while the translocation remained intact in ATM (Ataxia-Telangiectasia mutated)-deficient cells in response to UV irradiation. Moreover, we found that ATR is required for the UV-induced nuclear focus formation of XPA. Taken together, our results suggested that the ATR checkpoint pathway may modulate NER activity through the regulation of XPA redistribution in human cells upon UV irradiation.
- Published
- 2006
27. A new structural insight into XPA-DNA interactions
- Author
-
Benjamin Hilton, Steven M. Shell, Nick Shkriabai, Mamuka Kvaratskhelia, Phillip R. Musich, and Yue Zou
- Subjects
Models, Molecular ,lcsh:Life ,lcsh:QR1-502 ,NHS-biotin, N-hydroxysuccinimidobiotin ,Biochemistry ,lcsh:Microbiology ,chemistry.chemical_compound ,ds/ssDNA, double-strand/single-strand DNA ,DNA junction ,0303 health sciences ,Protein footprinting ,030302 biochemistry & molecular biology ,Xeroderma Pigmentosum Group A Protein ,DNA-Binding Proteins ,GGR, global genome repair ,Protein Binding ,endocrine system ,Xeroderma pigmentosum ,HMG-box ,DNA damage ,XPA ,Molecular Sequence Data ,Biophysics ,HGPS, Hutchinson–Gilford progeria syndrome ,Biology ,DNA-binding protein ,S2 ,TCR, transcription-coupled repair ,03 medical and health sciences ,RPA, replication protein A ,NER, nucleotide excision repair ,medicine ,Humans ,Binding site ,DNA-binding domain ,Molecular Biology ,030304 developmental biology ,Original Paper ,Binding Sites ,Base Sequence ,Lysine ,Cell Biology ,DNA ,Q-TOF, quadrupole time-of-flight ,medicine.disease ,nucleotide excision repair ,XPA, Xeroderma pigmentosum group A ,Protein Structure, Tertiary ,lcsh:QH501-531 ,chemistry ,XPA–DNA binding ,DBD, DNA-binding domain ,DTT, dithiothreitol ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,MALDI-TOF, matrix-assisted laser desorption time-of-flight ,Proteolysis ,Nucleic Acid Conformation ,Nucleotide excision repair - Abstract
XPA (xeroderma pigmentosum group A) protein is an essential factor for NER (nucleotide excision repair) which is believed to be involved in DNA damage recognition/verification, NER factor recruiting and stabilization of repair intermediates. Past studies on the structure of XPA have focused primarily on XPA interaction with damaged DNA. However, how XPA interacts with other DNA structures remains unknown though recent evidence suggest that these structures could be important for its roles in both NER and non-NER activities. Previously, we reported that XPA recognizes undamaged DNA ds/ssDNA (double-strand/single-strandDNA) junctions with a binding affinity much higher than its ability to bind bulky DNA damage. To understand how this interaction occurs biochemically we implemented a structural determination of the interaction using a MS-based protein footprinting method and limited proteolysis. By monitoring surface accessibility of XPA lysines to NHS-biotin modification in the free protein and the DNA junction-bound complex we show that XPA physically interacts with the DNA junctions via two lysines, K168 and K179, located in the previously known XPA(98–219) DBD (DNA-binding domain). Importantly, we also uncovered new lysine residues, outside of the known DBD, involved in the binding. We found that residues K221, K222, K224 and K236 in the C-terminal domain are involved in DNA binding. Limited proteolysis analysis of XPA–DNA interactions further confirmed this observation. Structural modelling with these data suggests a clamp-like DBD for the XPA binding to ds/ssDNA junctions. Our results provide a novel structure-function view of XPA–DNA junction interactions.
- Published
- 2014
28. Modulation of Replication Protein A Function by Its Hyperphosphorylation-induced Conformational Change Involving DNA Binding Domain B
- Author
-
Sonja Hess, Yue Zou, Mamuka Kvaratskhelia, Youxing Qu, and Yiyong Liu
- Subjects
Models, Molecular ,Conformational change ,Protein Conformation ,Oligonucleotides ,Biochemistry ,Mass Spectrometry ,Mice ,Phosphatidylinositol 3-Kinases ,Protein structure ,Chymotrypsin ,Phosphorylation ,Mice, Knockout ,Microscopy, Confocal ,Protein footprinting ,Stem Cells ,Tryptophan ,Recombinant Proteins ,DNA-Binding Proteins ,Plasmids ,Protein Binding ,Subcellular Fractions ,DNA damage ,Immunoblotting ,Molecular Sequence Data ,Biotin ,Hyperphosphorylation ,Palmitic Acids ,Biology ,Arginine ,complex mixtures ,Article ,Animals ,Amino Acid Sequence ,Molecular Biology ,Replication protein A ,Sequence Homology, Amino Acid ,Oligonucleotide ,Lysine ,Cell Membrane ,Proteins ,DNA ,Cell Biology ,DNA-binding domain ,Embryo, Mammalian ,Protein Structure, Tertiary ,enzymes and coenzymes (carbohydrates) ,Microscopy, Fluorescence ,Biophysics ,Protein Processing, Post-Translational ,DNA Damage - Abstract
Human replication protein A (RPA), composed of RPA70, RPA32, and RPA14 subunits, undergoes hyperphosphorylation in cells in response to DNA damage. Hyperphosphorylation that occurs predominately in the N-terminal region of RPA32 is believed to play a role in modulating the cellular activities of RPA essential for almost all DNA metabolic pathways. To understand how the hyperphosphorylation modulates the functions of RPA, we compared the structural characteristics of full-length native and hyperphosphorylated RPAs using mass spectrometric protein footprinting, fluorescence spectroscopy, and limited proteolysis. Our mass spectrometric data showed that of 24 lysines and 18 arginines readily susceptible to small chemical reagent modification in native RPA, the three residues Lys-343, Arg-335, and Arg-382, located in DNA binding domain B (DBD-B) of RPA70, were significantly shielded in the hyperphosphorylated protein. Tryptophan fluorescence studies indicated significant quenching of Trp-361, located in the DBD-B domain, induced by hyperphosphorylation of RPA. Consistently, DBD-B became more resistant to the limited proteolysis by chymotrypsin after RPA hyperphosphorylation. Taken together, our results indicate that upon hyperphosphorylation of RPA32 N terminus (RPA32N), RPA undergoes a conformational change involving the single-stranded DNA binding cleft of DBD-B. Comparison of the interactions of native and hyperphosphorylated RPAs with short single-stranded oligonucleotides or partial DNA duplexes with a short 5' or 3' single-stranded DNA tails showed reduced affinity for the latter protein. We propose that the hyperphosphorylation may play a role in modulating the cellular path-ways by altering the DBD-B-mediated RPA-DNA and RPA-protein interactions, hypothetically via the interaction of hyperphosphorylated RPA32N with DBD-B.
- Published
- 2005
29. Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein A in human cells
- Author
-
Xiaoming Wu, Yue Zou, and Steven M. Shell
- Subjects
DNA Replication ,Exonucleases ,Cancer Research ,DNA damage ,Cell Cycle Proteins ,Biology ,complex mixtures ,Article ,chemistry.chemical_compound ,Replication Protein A ,Genetics ,Humans ,RNA, Small Interfering ,Molecular Biology ,Replication protein A ,fungi ,Colocalization ,RNA ,G2-M DNA damage checkpoint ,Cell cycle ,Molecular biology ,Cell biology ,Chromatin ,DNA-Binding Proteins ,Genes, cdc ,enzymes and coenzymes (carbohydrates) ,Gene Expression Regulation ,chemistry ,Schizosaccharomyces pombe Proteins ,biological phenomena, cell phenomena, and immunity ,DNA ,DNA Damage ,HeLa Cells - Abstract
Replication protein A (RPA) is a eukaryotic single-stranded DNA-binding protein consisting of three subunits of 70-kDa, 32-kDa, and 14-kDa (RPA70, RPA32, RPA14, respectively). It is a protein essential for most cellular DNA metabolic pathways. Checkpoint proteins Rad9, Rad1 and Hus1 form a clamp-like complex which plays a central role in the DNA damage-induced checkpoint response. In this report, we presented the evidence that Rad9-Rad1-Hus1 complex directly interacted with RPA in human cells, and this interaction was mediated by the binding of Rad9 protein to both RPA70 and RPA32 subunits. In addition, the cellular interaction of Rad9-Rad1-Hus1 with RPA or hyperphosphorylated RPA was stimulated by UV irradiation or camptothecin treatment in a dose dependent manner. Such treatments also resulted in the co-localization of the nuclear foci formed with the two complexes. Consistently, knockdown of the RPA expression in cells by the small interference RNA (siRNA) blocked the DNA damage-dependent chromatin association of Rad9-Rad1-Hus1, and also inhibited the Rad9-Rad1-Hus1 complex formation. Taken together, our results suggest that Rad9-Rad1-Hus1 and RPA complexes collaboratively function in DNA damage responses, and that the RPA may serve as a regulator for the activity of Rad9-Rad1-Hus1 complex in the cellular checkpoint network.
- Published
- 2005
30. Interactions of human replication protein A with single-stranded DNA adducts
- Author
-
Yiyong Liu, Christopher Utzat, Nicholas E. Geacintov, Yu Liu, Yue Zou, Ashis K. Basu, and Zhengguan Yang
- Subjects
HMG-box ,DNA damage ,DNA repair ,Oligonucleotides ,DNA, Single-Stranded ,Electrophoretic Mobility Shift Assay ,complex mixtures ,Biochemistry ,DNA-binding protein ,DNA Adducts ,chemistry.chemical_compound ,Replication Protein A ,Humans ,Molecular Biology ,Replication protein A ,Molecular Structure ,Oligonucleotide ,Cell Biology ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,Spectrometry, Fluorescence ,chemistry ,DNA ,DNA Damage ,Protein Binding ,Research Article ,Nucleotide excision repair - Abstract
Human RPA (replication protein A), a single-stranded DNA-binding protein, is required for many cellular pathways including DNA repair, recombination and replication. However, the role of RPA in nucleotide excision repair remains elusive. In the present study, we have systematically examined the binding of RPA to a battery of well-defined ssDNA (single-stranded DNA) substrates using fluorescence spectroscopy. These substrates contain adducts of (6-4) photoproducts, N-acetyl-2-aminofluorene-, 1-aminopyrene-, BPDE (benzo[a]pyrene diol epoxide)- and fluorescein that are different in many aspects such as molecular structure and size, DNA disruption mode (e.g. base stacking or non-stacking), as well as chemical properties. Our results showed that RPA has a lower binding affinity for damaged ssDNA than for non-damaged ssDNA and that the affinity of RPA for damaged ssDNA depends on the type of adduct. Interestingly, the bulkier lesions have a greater effect. With a fluorescent base-stacking bulky adduct, (+)-cis-anti-BPDE-dG, we demonstrated that, on binding of RPA, the fluorescence of BPDE-ssDNA was significantly enhanced by up to 8–9-fold. This indicated that the stacking between the BPDE adduct and its neighbouring ssDNA bases had been disrupted and there was a lack of substantial direct contacts between the protein residues and the lesion itself. For RPA interaction with short damaged ssDNA, we propose that, on RPA binding, the modified base of ssDNA is looped out from the surface of the protein, permitting proper contacts of RPA with the remaining unmodified bases.
- Published
- 2005
31. Effects of DNA Adduct Structure and Sequence Context on Strand Opening of Repair Intermediates and Incision by UvrABC Nuclease
- Author
-
Ashis K. Basu, Christopher Utzat, Charlie Luo, Nicholas E. Geacintov, Zhengguan Yang, Yue Zou, and Steven M. Shell
- Subjects
chemistry.chemical_classification ,Endodeoxyribonucleases ,Base Sequence ,DNA Repair ,DNA repair ,Stereochemistry ,DNA damage ,Escherichia coli Proteins ,Molecular Sequence Data ,Electrophoretic Mobility Shift Assay ,Context (language use) ,Biochemistry ,Molecular biology ,Article ,Adduct ,DNA Adducts ,chemistry.chemical_compound ,chemistry ,DNA adduct ,Nucleotide ,DNA ,Nucleotide excision repair - Abstract
DNA damage recognition of nucleotide excision repair (NER) in Escherichia coli is achieved by at least two steps. In the first step, a helical distortion is recognized, which leads to a strand opening at the lesion site. The second step involves the recognition of the type of chemical modification in the single-stranded region of DNA during the processing of the lesions by UvrABC. In the current work, by comparing the efficiencies of UvrABC incision of several types of different DNA adducts, we show that the size and position of the strand opening are dependent on the type of DNA adducts. Optimal incision efficiency for the C8-guanine adducts of 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF) was observed in a bubble of three mismatched nucleotides, whereas the same for C8-guanine adduct of 1-nitropyrene and N(2)-guanine adducts of benzo[a]pyrene diol epoxide (BPDE) was noted in a bubble of six mismatched nucleotides. This suggests that the size of the aromatic ring system of the adduct might influence the extent and number of bases associated with the opened strand region catalyzed by UvrABC. We also showed that the incision efficiency of the AF or AAF adduct was affected by the neighboring DNA sequence context, which, in turn, was the result of differential binding of UvrA to the substrates. The sequence context effect on both incision and binding disappeared when a bubble structure of three bases was introduced at the adduct site. We therefore propose that these effects relate to the initial step of damage recognition of DNA structural distortion. The structure-function relationships in the recognition of the DNA lesions, based on our results, have been discussed.
- Published
- 2003
32. Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson-Gilford progeria syndrome
- Author
-
Hui Tang, Ding Zhi Fang, Yue Zou, Benjamin Hilton, and Phillip R. Musich
- Subjects
Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Progeria ,integumentary system ,DNA replication ,nutritional and metabolic diseases ,Cell Biology ,Biology ,RFC1 ,medicine.disease ,Progerin ,Molecular biology ,LMNA ,Replication factor C ,medicine ,Lamin - Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder because of a LMNA gene mutation that produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here, we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ~ 75 kDa, which appears to be defective in loading proliferating cell nuclear antigen (PCNA) and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Because of the crucial role of RFC in DNA replication, our findings provide a mechanistic interpretation for the observed early replicative arrest and premature aging phenotypes of HPGS and may lead to novel strategies in HGPS treatment. Furthermore, this unique truncated form of RFC1 may serve as a potential marker for HGPS.
- Published
- 2012
33. Recognition and incision of site-specifically modified C8 guanine adducts formed by 2-aminofluorene, N-acetyl-2-aminofluorene and 1-nitropyrene by UvrABC nuclease
- Author
-
Ramji Krishnasamy, Charlie Luo, Ashis K. Basu, and Yue Zou
- Subjects
Guanine ,DNA Repair ,DNA damage ,DNA repair ,DNA, Single-Stranded ,Biology ,Article ,Substrate Specificity ,DNA Adducts ,chemistry.chemical_compound ,DNA adduct ,Escherichia coli ,polycyclic compounds ,Genetics ,Nuclear Magnetic Resonance, Biomolecular ,Fluorenes ,Nuclease ,Endodeoxyribonucleases ,Pyrenes ,Base Sequence ,Oligonucleotide ,Escherichia coli Proteins ,2-Acetylaminofluorene ,Molecular biology ,DNA-Binding Proteins ,Kinetics ,Oligodeoxyribonucleotides ,chemistry ,biology.protein ,Nucleic Acid Conformation ,Thermodynamics ,DNA ,DNA Damage ,Mutagens ,Protein Binding ,Nucleotide excision repair - Abstract
Nucleotide excision repair plays a crucial role in removing many types of DNA adducts formed by UV light and chemical carcinogens. We have examined the interactions of Escherichia coli UvrABC nuclease proteins with three site-specific C8 guanine adducts formed by the carcinogens 2-aminofluorene (AF), N:-acetyl-2-acetylaminofluorene (AAF) and 1-nitropyrene (1-NP) in a 50mer oligonucleotide. Similar to the AF and AAF adducts, the 1-NP-induced DNA adduct contains an aminopyrene (AP) moiety covalently linked to the C8 position of guanine. The dissociation constants for UvrA binding to AF-, AAF- and AP-DNA adducts, determined by gel mobility shift assay, are 33 +/- 9, 8 +/- 2 and 23 +/- 9 nM, respectively, indicating that the AAF adduct is recognized much more efficiently than the other two. Incision by UvrABC nuclease showed that AAF-DNA was cleaved approximately 2-fold more efficiently than AF- or AP-DNA (AAF > AF approximately AP), even though AP has the largest molecular size in this group. However, an opened DNA structure of six bases around the adduct increased the incision efficiency for AF-DNA (but not for AP-DNA), making it equivalent to that for AAF-DNA. These results are consistent with a model in which DNA damage recognition by the E. coli nucleotide excision repair system consists of two sequential steps. It includes recognition of helical distortion in duplex DNA followed by recognition of the type of nucleotide chemical modification in a single-stranded region. The difference in incision efficiency between AF- and AAF-DNA adducts in normal DNA sequence, therefore, is a consequence of their difference in inducing structural distortions in DNA. The results of this study are discussed in the light of NMR solution structures of these DNA adducts.
- Published
- 2000
34. Butadiene-induced Intrastrand DNA Cross-links: A Possible Role in Deletion Mutagenesis
- Author
-
Constance M. Harris, Bennett Van Houten, J. Russ Carmical, Agnieszka Kowalczyk, R. Stephen Lloyd, Yue Zou, Lubomir V. Nechev, and Thomas M. Harris
- Subjects
DNA, Complementary ,Guanine ,Molecular Sequence Data ,Oligonucleotides ,Biochemistry ,DNA Adducts ,chemistry.chemical_compound ,Bacterial Proteins ,Butadienes ,Escherichia coli ,Humans ,Molecular Biology ,Chromatography, High Pressure Liquid ,Polymerase ,Adenosine Triphosphatases ,Base Sequence ,biology ,Escherichia coli Proteins ,DNA replication ,Nucleic Acid Hybridization ,Stereoisomerism ,DNA ,Cell Biology ,Transfection ,Molecular biology ,Deletion Mutagenesis ,DNA-Binding Proteins ,Cross-Linking Reagents ,Genes, ras ,chemistry ,Mutagenesis ,Duplex (building) ,biology.protein ,Epoxy Compounds ,Gene Deletion ,Mutagens ,Nucleotide excision repair - Abstract
To initiate studies designed to identify the mutagenic spectrum associated with butadiene diepoxide-induced N(2)-N(2) guanine intrastrand cross-links, site specifically adducted oligodeoxynucleotides were synthesized in which the adducted bases were centrally located within the context of the human ras 12 codon. The two stereospecifically modified DNAs and the corresponding unmodified DNA were ligated into a single-stranded M13mp7L2 vector and transfected into Escherichia coli. Both stereoisomeric forms (R, R and S,S) of the DNA cross-links resulted in very severely decreased plaque-forming ability, along with an increased mutagenic frequency for both single base substitutions and deletions compared with unadducted DNAs, with the S,S stereoisomer being the most mutagenic. Consistent with decreased plaque formation, in vitro replication of DNA templates containing the cross-links by the three major E. coli polymerases revealed replication blockage by both stereoisomeric forms of the cross-links. The same DNAs that were used for replication studies were also assembled into duplex DNAs and tested as substrates for the initiation of nucleotide excision repair by the E. coli UvrABC complex. UvrABC incised linear substrates containing these intrastrand cross-links with low efficiency, suggesting that these lesions may be inefficiently repaired by the nucleotide excision repair system.
- Published
- 2000
35. Involvement of Molecular Chaperonins in Nucleotide Excision Repair
- Author
-
Bennett Van Houten, Yue Zou, and David J. Crowley
- Subjects
Strain (chemistry) ,DNA damage ,Pyrimidine dimer ,Cell Biology ,Biology ,Biochemistry ,In vitro ,Chaperonin ,chemistry.chemical_compound ,chemistry ,biological sciences ,Ultraviolet light ,bacteria ,Guanidine ,Molecular Biology ,Nucleotide excision repair - Abstract
UvrA is one of the key Escherichia coli proteins involved in removing DNA damage during the process of nucleotide excision repair. The relatively low concentrations (nanomolar) of the protein in the normal cells raise the potential questions about its stability in vivo under both normal and stress conditions. In vitro, UvrA at low concentrations is shown to be stabilized to heat inactivation by E. colimolecular chaperones DnaK or the combination of DnaK, DnaJ, and GrpE. These chaperone proteins allow sub-nanomolar concentrations of UvrA to load UvrB through >10 cycles of incision. Guanidine hydrochloride-denatured UvrA was reactivated by DnaK, DnaJ, and GrpE to as much as 50% of the native protein activity. Co-immunoprecipitation assays showed that DnaK bound denatured UvrA in the absence of ATP. UV survival studies of a DnaK-deficient strain indicated an 80-fold increased sensitivity to 100 J/m2 of ultraviolet light (254 nm) as compared with an isogenic wild-type strain. Global repair analysis indicated a reduction in the extent of pyrimidine dimer and 6–4 photoproduct removal in the DnaK-deficient cells. These results suggest that molecular chaperonins participate in nucleotide excision repair by maintaining repair proteins in their properly folded state.
- Published
- 1998
36. Formation of DNA Repair Intermediates and Incision by the ATP-dependent UvrB-UvrC Endonuclease
- Author
-
Randall K. Walker, Heather Bassett, Nicholas E. Geacintov, Bennett Van Houten, and Yue Zou
- Subjects
DNA, Bacterial ,DNA Repair ,DNA repair ,DNA damage ,Molecular Sequence Data ,Biochemistry ,Adduct ,chemistry.chemical_compound ,Endonuclease ,Bacterial Proteins ,Escherichia coli ,A-DNA ,Nucleotide ,Molecular Biology ,chemistry.chemical_classification ,Endodeoxyribonucleases ,Base Sequence ,biology ,Chemistry ,Escherichia coli Proteins ,DNA Helicases ,Cell Biology ,Endonucleases ,Molecular biology ,Biophysics ,biology.protein ,DNA ,Nucleotide excision repair - Abstract
The Escherichia coli UvrB and UvrC proteins play key roles in DNA damage processing and incisions during nucleotide excision repair. To study the DNA structural requirements and protein-DNA intermediates formed during these processes, benzo[a]pyrene diol epoxide-damaged and structure-specific 50-base pair substrates were constructed. DNA fragments containing a preexisting 3' incision were rapidly and efficiently incised 5' to the adduct. Gel mobility shift assays indicated that this substrate supported UvrA dissociation from the UvrB-DNA complex, which led to efficient incision. Experiments with a DNA fragment containing an internal noncomplementary 11-base region surrounding the benzo[a]pyrene diol epoxide adduct indicated that UvrABC nuclease does not require fully duplexed DNA for binding and incision. In the absence of UvrA, UvrB (UvrC) bound to an 11-base noncomplementary region containing a 3' nick (Y substrate), forming a stable protein-DNA complex (Kd approximately 5-10 nM). Formation of this complex was absolutely dependent upon UvrC. Addition to this complex of ATP, but not adenosine 5'-(beta,gamma-iminotriphosphate) or adenosine 5'-(beta, gamma-methylene)triphosphate, caused incision three or four nucleotides 5' to the double strand-single strand junction. The ATPase activity of native UvrB is activated upon interaction with UvrC and enhanced further by the addition of Y substrate. Incision of this Y structure occurs even without DNA damage. Thus the UvrBC complex is a structure-specific, ATP-dependent endonuclease.
- Published
- 1997
37. UV-induced nuclear import of XPA is mediated by importin-α4 in an ATR-dependent manner
- Author
-
Yue Zou, Phillip R. Musich, Zhengke Li, Brian M. Cartwright, and Hui Wang
- Subjects
alpha Karyopherins ,Small interfering RNA ,endocrine system ,Xeroderma pigmentosum ,animal structures ,Ultraviolet Rays ,DNA damage ,Immunoprecipitation ,Nuclear Localization Signals ,Biophysics ,Active Transport, Cell Nucleus ,DNA repair ,lcsh:Medicine ,Ataxia Telangiectasia Mutated Proteins ,Importin ,Biology ,Biochemistry ,Models, Biological ,environment and public health ,Cell Line ,03 medical and health sciences ,Molecular cell biology ,0302 clinical medicine ,GTP-Binding Proteins ,medicine ,Humans ,lcsh:Science ,Cellular Stress Responses ,030304 developmental biology ,Cell Nucleus ,0303 health sciences ,Multidisciplinary ,Physics ,lcsh:R ,DNA ,medicine.disease ,Molecular biology ,Recombinant Proteins ,Xeroderma Pigmentosum Group A Protein ,Nucleic acids ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,lcsh:Q ,Nuclear transport ,Nuclear localization sequence ,Research Article ,Protein Binding ,Nucleotide excision repair - Abstract
Xeroderma pigmentosum Group A (XPA) is a crucial factor in mammalian nucleotide excision repair (NER) and nuclear import of XPA from the cytoplasm for NER is regulated in cellular DNA damage responses in S-phase. In this study, experiments were carried out to determine the transport mechanisms that are responsible for the UV (ultraviolet)-induced nuclear import of XPA. We found that, in addition to the nuclear localization signal (NLS) of XPA, importin-α4 or/and importin-α7 are required for the XPA nuclear import. Further investigation indicated that, importin-α4 and importin-α7 directly interacted with XPA in cells. Interestingly, the binding of importin-α4 to XPA was dependent on UV-irradiation, while the binding of importin-α7 was not, suggesting a role for importin-α7 in nuclear translocation of XPA in the absence of DNA damage, perhaps with specificity to certain non-S-phases of the cell-cycle. Consistent with the previous report of a dependence of UV-induced XPA nuclear import on ataxia telangiectasia and Rad3-related protein (ATR) in S-phase, knockdown of ATR reduced the amount of XPA interacting with importin-α4. In contrast, the GTPase XPA binding protein 1 (XAB1), previously proposed to be required for XPA nuclear import, showed no effect on the nuclear import of XPA in our siRNA knockdown analysis. In conclusion, our results suggest that upon DNA damage transport adaptor importin-α4 imports XPA into the nucleus in an ATR-dependent manner, while XAB1 has no role in this process. In addition, these findings reveal a potential new therapeutic target for the sensitization of cancer cells to chemotherapy.
- Published
- 2013
38. Replication-mediated disassociation of replication protein A-XPA complex upon DNA damage: implications for RPA handing off
- Author
-
Xiaoming Wu, Yue Zou, and Gaofeng Jiang
- Subjects
DNA Replication ,endocrine system ,Xeroderma pigmentosum ,Cell cycle checkpoint ,DNA Repair ,DNA damage ,DNA repair ,Ultraviolet Rays ,DNA, Single-Stranded ,Down-Regulation ,Biology ,complex mixtures ,Article ,chemistry.chemical_compound ,Cell Line, Tumor ,Replication Protein A ,medicine ,Humans ,Hydroxyurea ,Phosphorylation ,Replication protein A ,DNA replication ,Cell Biology ,General Medicine ,Cell Cycle Checkpoints ,DNA ,medicine.disease ,Molecular biology ,Cell biology ,Xeroderma Pigmentosum Group A Protein ,enzymes and coenzymes (carbohydrates) ,chemistry ,Camptothecin ,Nucleotide excision repair ,DNA Damage ,Protein Binding - Abstract
RPA (replication protein A), the eukaryotic ssDNA (single-stranded DNA)-binding protein, participates in most cellular processes in response to genotoxic insults, such as NER (nucleotide excision repair), DNA, DSB (double-strand break) repair and activation of cell cycle checkpoint signalling. RPA interacts with XPA (xeroderma pigmentosum A) and functions in early stage of NER. We have shown that in cells the RPA-XPA complex disassociated upon exposure of cells to high dose of UV irradiation. The dissociation required replication stress and was partially attributed to tRPA hyperphosphorylation. Treatment of cells with CPT (camptothecin) and HU (hydroxyurea), which cause DSB DNA damage and replication fork collapse respectively and also leads to the disruption of RPA-XPA complex. Purified RPA and XPA were unable to form complex in vitro in the presence of ssDNA. We propose that the competition-based RPA switch among different DNA metabolic pathways regulates the dissociation of RPA with XPA in cells after DNA damage. The biological significances of RPA-XPA complex disruption in relation with checkpoint activation, DSB repair and RPA hyperphosphorylation are discussed.
- Published
- 2012
39. (5'S)-8,5'-cyclo-2'-deoxyguanosine is a strong block to replication, a potent pol V-dependent mutagenic lesion, and is inefficiently repaired in Escherichia coli
- Author
-
Benjamin Hilton, Rajat S. Das, Yue Zou, Ashis K. Basu, Vijay P. Jasti, and Savithri Weerasooriya
- Subjects
DNA Replication ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Repair ,DNA polymerase ,DNA repair ,Biochemistry ,DNA polymerase delta ,Cockayne syndrome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Escherichia coli ,Deoxyguanosine ,skin and connective tissue diseases ,SOS Response, Genetics ,030304 developmental biology ,0303 health sciences ,biology ,Rapid Report ,DNA replication ,nutritional and metabolic diseases ,Base excision repair ,DNA-Directed RNA Polymerases ,medicine.disease ,Molecular biology ,3. Good health ,chemistry ,Mutagenesis ,030220 oncology & carcinogenesis ,biology.protein ,Nucleotide excision repair - Abstract
8,5′-Cyclopurines, making up an important class of ionizing radiation-induced tandem DNA damage, are repaired only by nucleotide excision repair (NER). They accumulate in NER-impaired cells, as in Cockayne syndrome group B and certain Xeroderma Pigmentosum patients. A plasmid containing (5′S)-8,5′-cyclo-2′-deoxyguanosine (S-cdG) was replicated in Escherichia coli with specific DNA polymerase knockouts. Viability was S-cdA > S-cdG. In summary, S-cdG is a major block to DNA replication, highly mutagenic, and repaired slowly in E. coli.
- Published
- 2011
40. EPR studies of spin-labeled bovine plasma amine oxidase: The nature of the substrate-binding site
- Author
-
Joseph W. Poku, Coleen Young O’Gara, Jose M. Marchena, Javier G. Urtiaga, Frederick T. Greenaway, and Yue Zou
- Subjects
Amine oxidase ,Macromolecular Substances ,Dimer ,Biophysics ,Analytical chemistry ,chemistry.chemical_element ,Biochemistry ,law.invention ,Cyclic N-Oxides ,chemistry.chemical_compound ,law ,Animals ,Spin label ,Electron paramagnetic resonance ,Molecular Biology ,Oxidoreductases Acting on CH-NH Group Donors ,Binding Sites ,biology ,Electron Spin Resonance Spectroscopy ,Amine oxidase (copper-containing) ,Substrate (chemistry) ,Active site ,Copper ,Kinetics ,Crystallography ,chemistry ,biology.protein ,Cattle ,Spin Labels ,Amine Oxidase (Copper-Containing) - Abstract
The carbonyl cofactor of bovine plasma amine oxidase (EC 1.4.3.6), recently shown to be 6-hydroxydopa (also known as topa), has been spin labeled to the extent of one label per enzyme dimer molecule, using 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl (4-amino-TEMPO) and 4-hydrazino-TEMPO followed by reduction with borohydride. By studying the EPR spectra of the labeled enzyme, it has been deduced that there is no magnetic interaction between the copper and the spin label, and that the spin label is at least 1.3 nm distant from the copper(II) ion in the resting enzyme. The bound label is strongly immobilized, is in a sterically constricted environment, and is not accessible to small anions. Removal of the copper does not alter the EPR spectrum of the label. The results are similar to results for porcine plasma amine oxidase, and show that the copper is not close to, and does not directly interact with, the topa-bound substrate.
- Published
- 1991
41. Other Proteins Interacting with XP Proteins
- Author
-
Yue Zou and Steven M. Shell
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Xeroderma pigmentosum ,DNA Repair ,DNA repair ,DNA damage ,DNA-Directed DNA Polymerase ,Article ,chemistry.chemical_compound ,medicine ,Humans ,Protein–DNA interaction ,skin and connective tissue diseases ,Xeroderma Pigmentosum Group D Protein ,biology ,Nuclear Proteins ,Proteins ,nutritional and metabolic diseases ,Helicase ,Endonucleases ,medicine.disease ,Molecular biology ,Xeroderma Pigmentosum Group A Protein ,Cell biology ,DNA-Binding Proteins ,chemistry ,biology.protein ,Transcription factor II H ,DNA ,Transcription Factors ,Nucleotide excision repair - Abstract
Genetic defects in Nucleotide excision repair (NER) lead to the clinical disorder xeroderma pigmentosum (XP) in humans which is characterized by dramatically increased sensitivity to UV light and a predisposition to development of skin cancers.1,2 NER is a major mechanism of DNA repair in cells for the removal of a large variety of bulky DNA lesions induced by environmental genotoxic agents and chemicals. The molecular basis of XP has been attributed to mutations in any of the eight XP genes, XPA through G whose products are required for NER-mediated removal of DNA damage and XP-variant (XPV). The XP proteins involved in NER can be divided into three groups based on their activity in the NER process. XPA, XPC and XPE are required for sensing DNA damage and initiating the repair process. XPB and XPD, components of the basal transcription factor TFIIH, are helicases that create a DNA strand opening surrounding the adducted base(s) during NER. XPG and XPF are the endonucleases that perform the dual incisions to release the damaged strand and allow resynthesis using the nondamaged strand as a template.3, 4, 5 Protein-protein interactions are integral for the correct assembly of the pre-incision complex and for the positioning of the nucleases prior to incision. However, these proteins have been found to form complexes with other proteins not directly involved in the NER mechanism. This chapter describes these proteins and their interactions and discusses their effects on the XP proteins, DNA repair, and genome stability.
- Published
- 2008
42. Involvement of Xeroderma Pigmentosum Group A (XPA) in Progeria Arising from Defective Maturation of Prelamin A
- Author
-
Michael S. Sinensky, Yiyong Liu, Steven M. Shell, Antonio E. Rusiñol, Yue Zou, Youjie Wang, and Ji Liu
- Subjects
Premature aging ,Genome instability ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Xeroderma pigmentosum ,DNA Repair ,DNA damage ,DNA repair ,genetic processes ,Biology ,Biochemistry ,Article ,Progeria ,Genetics ,medicine ,Humans ,Protein Precursors ,Molecular Biology ,Cells, Cultured ,integumentary system ,Nuclear Proteins ,DNA ,medicine.disease ,Lamin Type A ,Molecular biology ,Xeroderma Pigmentosum Group A Protein ,enzymes and coenzymes (carbohydrates) ,RNA Interference ,biological phenomena, cell phenomena, and immunity ,Lamin ,Biotechnology ,Nucleotide excision repair ,DNA Damage ,Protein Binding - Abstract
Cellular accumulation of DNA damage has been widely implicated in cellular senescence, aging, and premature aging. In Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD), premature aging is linked to accumulation of DNA double-strand breaks (DSBs), which results in genome instability. However, how DSBs accumulate in cells despite the presence of intact DNA repair proteins remains unknown. Here we report that the recruitment of DSB repair factors Rad50 and Rad51 to the DSB sites, as marked by gamma-H2AX, was impaired in human HGPS and Zmpste24-deficient cells. Consistently, the progeria-associated DSBs appeared to be unrepairable although DSBs induced by camptothecin were efficiently removed in the progeroid cells. We also found that these progeroid cells exhibited nuclear foci of xeroderma pigmentosum group A (XPA), a unique nucleotide excision repair protein. Strikingly, these XPA foci colocalized with the DSB sites in the progeroid cells. This XPA-DSB association was further confirmed and found to be mediated by DNA, using a modified chromatin immunoprecipitation assay and coimmunoprecipitation. RNA interference (RNAi) knockdown of XPA in HGPS cells partially restored DSB repair as evidenced by Western blot analysis, immunofluorescence and comet assays. We propose that the uncharacteristic localization of XPA to or near DSBs inhibits DSB repair, thereby contributing to the premature aging phenotypes observed in progeria arising from genetic defects in prelamin A maturation.
- Published
- 2007
43. Structural characterization of human RPA sequential binding to single-stranded DNA using ssDNA as a molecular ruler
- Author
-
Ying Xu, Zhengguan Yang, Yue Zou, Youxing Qu, Marina Roginskaya, and Lifeng Cai
- Subjects
Models, Molecular ,Mutation ,Binding Sites ,DNA, Single-Stranded ,Plasma protein binding ,Biology ,medicine.disease_cause ,Biochemistry ,Molecular biology ,Article ,Protein Structure, Tertiary ,enzymes and coenzymes (carbohydrates) ,chemistry.chemical_compound ,Spectrometry, Fluorescence ,chemistry ,Replication Protein A ,Biophysics ,medicine ,Humans ,Binding site ,Replication protein A ,DNA ,Protein Binding - Abstract
Human replication protein A (RPA), a heterotrimer composed of RPA70, RPA32, and RPA14 subunits, contains four single-stranded DNA (ssDNA) binding domains (DBD): DBD-A, DBD-B, and DBD-C in RPA70 and DBD-D in RPA32. Although crystallographic or NMR structures of these DBDs and a trimerization core have been determined, the structure of the full length of RPA or the RPA-ssDNA complex remains unknown. In this article, we have examined the structural features of RPA interaction with ssDNA by fluorescence spectroscopy. Using a set of oligonucleotides (dT) with varying lengths as a molecular ruler and also as the substrate, we have determined at single-nucleotide resolution the relative positions of the ssDNA with interacting intrinsic tryptophans of RPA. Our results revealed that Trp528 in DBD-C and Trp107 in DBD-D contact ssDNA at the 16th and 24th nucleotides (nt) from the 5'-end of the substrate, respectively. Evaluation of the relative spatial arrangement of RPA domains in the RPA-ssDNA complex suggested that DBD-B and DBD-C are spaced by about 4 nt ( approximately 19 A) apart, whereas DBD-C and DBD-D are spaced by about 7 nt ( approximately 34 A). On the basis of these geometric constraints, a global structure model for the binding of the major RPA DBDs to ssDNA was proposed.
- Published
- 2007
44. Molecular evidence of the involvement of the nucleotide excision repair (NER) system in the repair of the mono(ADP-ribosyl)ated DNA adduct produced by pierisin-1, an apoptosis-inducing protein from the cabbage butterfly
- Author
-
Yasuko Matsumoto, Masahiko Watanabe, Takashi Yagi, Keiji Wakabayashi, Yue Zou, Kazuki Matsukawa, Takeji Takamura-Enya, Kiyoji Tanaka, Takashi Sugimura, Isao Kuraoka, Masanobu Kawanishi, and Yukari Totsuka
- Subjects
DNA Replication ,DNA Repair ,DNA repair ,Apoptosis ,Biology ,Toxicology ,medicine.disease_cause ,Catalysis ,Cell Line ,chemistry.chemical_compound ,DNA Adducts ,DNA adduct ,medicine ,Deoxyguanosine ,Animals ,Humans ,Escherichia coli ,Gel electrophoresis ,ADP Ribose Transferases ,Mutation ,Endodeoxyribonucleases ,Molecular Structure ,Nucleotides ,Escherichia coli Proteins ,General Medicine ,Molecular biology ,Xeroderma Pigmentosum Group A Protein ,Adenosine Diphosphate ,chemistry ,Biochemistry ,Insect Proteins ,Apoptosis Regulatory Proteins ,Butterflies ,DNA ,Nucleotide excision repair ,Plasmids - Abstract
Pierisin-1 is a potent apoptosis-inducing protein found in the pupal extract of the cabbage white butterfly. Pierisin-1 catalyzes the mono(ADP-ribosyl)ation of the 2'-deoxyguanosine residue and produces a bulky adduct, N2-(ADP-ribos-1-yl)-2'-deoxyguanosine (N2-ADPR-dG) in DNA. Here, we examined the involvement of the nucleotide excision repair (NER) system in the removal of N2-ADPR-dG in Escherichia coli (E. coli) and human cells. The results of mobility shift gel electrophoresis assays using a 50-mer oligodeoxynucleotide containing a single N2-ADPR-dG showed that E. coli UvrAB proteins bound to the N2-ADPR-dG in vitro. Incubation of the adducted oligodeoxynucleotides with UvrABC resulted in the incision of the oligonucleotides in vitro. The results of filter binding and gel mobility shift assays using human XPA protein showed that XPA bound to DNA containing N2-ADPR-dGs in vitro. Finally, we introduced plasmids containing N2-ADPR-dGs into E. coli and human cells. N2-ADPR-adducted plasmids replicated l0 times and 20 times less efficiently in NER-deficient E. coli and human cells than in their wild-type counterparts, respectively. More mutations were induced in the plasmid propagated in NER-deficient cells than that in wild-type human cells. These results indicate the involvement of the NER system in the repair of N2-ADPR-dG in both E. coli and human cells.
- Published
- 2007
45. Abstract A34: MC1R signaling reduces UV mutagenesis by ATR-mediated recruitment of XPA to photolesions
- Author
-
Perry A. Christian, John A. D'Orazio, Jillian C. Vanover, Yue Zou, Stuart G. Jarrett, Erin M. Wolf Horrell, and Mary C. Boulanger
- Subjects
Cancer Research ,Xeroderma pigmentosum ,DNA repair ,Mutagenesis ,Biology ,medicine.disease ,Molecular biology ,Oncology ,Ataxia-telangiectasia ,medicine ,Phosphorylation ,Protein kinase A ,Nucleotide excision repair ,Melanocortin 1 receptor - Abstract
The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic Gs-coupled transmembrane receptor activated by binding to its high-affinity ligand, α-melanocyte stimulating hormone (MSH). Besides influencing pigment phenotype and mediating adaptive tanning, MC1R signaling is intricately linked with genome maintenance and DNA repair. Individuals harboring loss-of-function MC1R polymorphisms are UV sensitive and melanoma-prone. We have determined that MC1R-mediated cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435 which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing UV mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA and elevates UV-induced mutagenesis. PKA-mediated ATR phosphorylation on Ser435 appears to induce a DNA repair-specific function of ATR independent of Chk1 phosphorylation and cell cycle arrest. Importantly, MC1R signaling defects and sub-optimal DNA repair are overcome by forskolin-mediated cAMP induction in melanocytes and in whole skin. Our findings mechanistically link cAMP-PKA signaling to NER and illustrate the potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals. Citation Format: Stuart Gordon Jarrett, Erin M. Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue Zou, John August D'Orazio. MC1R signaling reduces UV mutagenesis by ATR-mediated recruitment of XPA to photolesions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A34.
- Published
- 2015
46. DNA damage responses caused by Zmpste24 deficiency and lamin A mutation in premature ageing
- Author
-
yiyong liu and yue zou
- Subjects
DNA damage ,Mutation (genetic algorithm) ,Genetics ,Biology ,Molecular Biology ,Biochemistry ,Molecular biology ,Premature ageing ,Lamin ,Biotechnology - Published
- 2006
47. A quantitative analysis of secondary RNA structure using domination based parameters on trees
- Author
-
Yue Zou, Debra J. Knisley, Edith Seier, and Teresa W. Haynes
- Subjects
Models, Molecular ,Theoretical computer science ,Domination analysis ,Computer science ,lcsh:Computer applications to medicine. Medical informatics ,Biochemistry ,RNA Motifs ,Structural Biology ,Dual graph ,Computer Simulation ,Nucleic acid structure ,Invariant (mathematics) ,Molecular Biology ,lcsh:QH301-705.5 ,Sequence Analysis, RNA ,Applied Mathematics ,Graph theory ,Graph ,Computer Science Applications ,ComputingMethodologies_PATTERNRECOGNITION ,Models, Chemical ,lcsh:Biology (General) ,Nucleic Acid Conformation ,RNA ,lcsh:R858-859.7 ,Sequence Alignment ,Algorithms ,Research Article - Abstract
Background It has become increasingly apparent that a comprehensive database of RNA motifs is essential in order to achieve new goals in genomic and proteomic research. Secondary RNA structures have frequently been represented by various modeling methods as graph-theoretic trees. Using graph theory as a modeling tool allows the vast resources of graphical invariants to be utilized to numerically identify secondary RNA motifs. The domination number of a graph is a graphical invariant that is sensitive to even a slight change in the structure of a tree. The invariants selected in this study are variations of the domination number of a graph. These graphical invariants are partitioned into two classes, and we define two parameters based on each of these classes. These parameters are calculated for all small order trees and a statistical analysis of the resulting data is conducted to determine if the values of these parameters can be utilized to identify which trees of orders seven and eight are RNA-like in structure. Results The statistical analysis shows that the domination based parameters correctly distinguish between the trees that represent native structures and those that are not likely candidates to represent RNA. Some of the trees previously identified as candidate structures are found to be "very" RNA like, while others are not, thereby refining the space of structures likely to be found as representing secondary RNA structure. Conclusion Search algorithms are available that mine nucleotide sequence databases. However, the number of motifs identified can be quite large, making a further search for similar motif computationally difficult. Much of the work in the bioinformatics arena is toward the development of better algorithms to address the computational problem. This work, on the other hand, uses mathematical descriptors to more clearly characterize the RNA motifs and thereby reduce the corresponding search space. These preliminary findings demonstrate that graph-theoretic quantifiers utilized in fields such as computer network design hold significant promise as an added tool for genomics and proteomics.
- Published
- 2006
48. Modulation of Replication Protein A (RPA) Function by Its Hyperphosphorylation‐Induced Conformational Change Involving DNA Binding Domain B
- Author
-
yiyong liu and yue zou
- Subjects
Conformational change ,HMG-box ,Chemistry ,Ter protein ,Hyperphosphorylation ,DNA-binding domain ,Biochemistry ,Replication factor C ,Genetics ,Biophysics ,Molecular Biology ,Replication protein A ,Biotechnology ,Binding domain - Published
- 2006
49. Preferential localization of hyperphosphorylated replication protein A to double-strand break repair and checkpoint complexes upon DNA damage
- Author
-
Yue Zou, Zhengguan Yang, Xiaoming Wu, and Yiyong Liu
- Subjects
Cell cycle checkpoint ,Lung Neoplasms ,DNA Repair ,DNA damage ,Ultraviolet Rays ,Protein subunit ,RAD52 ,genetic processes ,RAD51 ,Adenocarcinoma ,Biochemistry ,complex mixtures ,Cell Line, Tumor ,Replication Protein A ,Humans ,Phosphorylation ,Molecular Biology ,Replication protein A ,Chemistry ,Cell Biology ,G2-M DNA damage checkpoint ,Molecular biology ,Double Strand Break Repair ,Rad52 DNA Repair and Recombination Protein ,enzymes and coenzymes (carbohydrates) ,Protein Transport ,Gene Expression Regulation ,Rad51 Recombinase ,biological phenomena, cell phenomena, and immunity ,DNA Damage ,Protein Binding ,Research Article - Abstract
RPA (replication protein A) is an essential factor for DNA DSB (double-strand break) repair and cell cycle checkpoint activation. The 32 kDa subunit of RPA undergoes hyperphosphorylation in response to cellular genotoxic insults. However, the potential involvement of hyperphosphorylated RPA in DSB repair and checkpoint activation remains unclear. Using co-immunoprecipitation assays, we showed that cellular interaction of RPA with two DSB repair factors, Rad51 and Rad52, was predominantly mediated by the hyperphosphorylated species of RPA in cells after UV and camptothecin treatment. Moreover, Rad51 and Rad52 displayed higher affinity for the hyperphosphorylated RPA than native RPA in an in vitro binding assay. Checkpoint kinase ATR (ataxia telangiectasia mutated and Rad3-related) also interacted more efficiently with the hyperphosphorylated RPA than with native RPA following DNA damage. Consistently, immunofluorescence microscopy demonstrated that the hyperphosphorylated RPA was able to co-localize with Rad52 and ATR to form significant nuclear foci in cells. Our results suggest that hyperphosphorylated RPA is preferentially localized to DSB repair and the DNA damage checkpoint complexes in response to DNA damage.
- Published
- 2005
50. Involvement of the nucleotide excision repair protein UvrA in instability of CAG*CTG repeat sequences in Escherichia coli
- Author
-
Vladimir N. Potaman, Yue Zou, Vera I. Hashem, Richard R. Sinden, and Elena A. Oussatcheva
- Subjects
DNA, Bacterial ,DNA Repair ,DNA damage ,DNA repair ,Biology ,Biochemistry ,chemistry.chemical_compound ,Replication slippage ,Plasmid ,Bacterial Proteins ,Trinucleotide Repeats ,Escherichia coli ,Molecular Biology ,Genetics ,Adenosine Triphosphatases ,Escherichia coli Proteins ,Nucleic Acid Heteroduplexes ,Cell Biology ,Molecular biology ,DNA-Binding Proteins ,chemistry ,bacteria ,Trinucleotide repeat expansion ,DNA ,Nucleotide excision repair ,Heteroduplex ,Plasmids - Abstract
Several human genetic diseases have been associated with the genetic instability, specifically expansion, of trinucleotide repeat sequences such as (CTG)(n).(CAG)(n). Molecular models of repeat instability imply replication slippage and the formation of loops and imperfect hairpins in single strands. Subsequently, these loops or hairpins may be recognized and processed by DNA repair systems. To evaluate the potential role of nucleotide excision repair in repeat instability, we measured the rates of repeat deletion in wild type and excision repair-deficient Escherichia coli strains (using a genetic assay for deletions). The rate of triplet repeat deletion decreased in an E. coli strain deficient in the damage recognition protein UvrA. Moreover, loops containing 23 CTG repeats were less efficiently excised from heteroduplex plasmids after their transformation into the uvrA(-) strain. As a result, an increased proportion of plasmids containing the full-length repeat were recovered after the replication of heteroduplex plasmids containing unrepaired loops. In biochemical experiments, UvrA bound to heteroduplex substrates containing repeat loops of 1, 2, or 17 CAG repeats with a K(d) of about 10-20 nm, which is an affinity about 2 orders of magnitude higher than that of UvrA bound to the control substrates containing (CTG)(n).(CAG)(n) in the linear form. These results suggest that UvrA is involved in triplet repeat instability in cells. Specifically, UvrA may bind to loops formed during replication slippage or in slipped strand DNA and initiate DNA repair events that result in repeat deletion. These results imply a more comprehensive role for UvrA, in addition to the recognition of DNA damage, in maintaining the integrity of the genome.
- Published
- 2001
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