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921 results on '"Chen, David J."'

3. The Interaction of CtIP and Nbs1 Connects CDK and ATM to Regulate HR–Mediated Double-Strand Break Repair

Author

Wang, Hailong, Shi, Linda Z, Wong, Catherine CL, Han, Xuemei, Hwang, Patty Yi-Hwa, Truong, Lan N, Zhu, Qingyuan, Shao, Zhengping, Chen, David J, Berns, Michael W, Yates, John R, Chen, Longchuan, and Wu, Xiaohua

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Women's Health, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cyclin-Dependent Kinases, DNA Breaks, Double-Stranded, DNA Repair, DNA-Binding Proteins, Endodeoxyribonucleases, Genomic Instability, HEK293 Cells, HeLa Cells, Homologous Recombination, Humans, Nuclear Proteins, Phosphorylation, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins, Hela Cells, Developmental Biology
Abstract

CtIP plays an important role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair and interacts with Nbs1 and BRCA1, which are linked to Nijmegen breakage syndrome (NBS) and familial breast cancer, respectively. We identified new CDK phosphorylation sites on CtIP and found that phosphorylation of these newly identified CDK sites induces association of CtIP with the N-terminus FHA and BRCT domains of Nbs1. We further showed that these CDK-dependent phosphorylation events are a prerequisite for ATM to phosphorylate CtIP upon DNA damage, which is important for end resection to activate HR by promoting recruitment of BLM and Exo1 to DSBs. Most notably, this CDK-dependent CtIP and Nbs1 interaction facilitates ATM to phosphorylate CtIP in a substrate-specific manner. These studies reveal one important mechanism to regulate cell-cycle-dependent activation of HR upon DNA damage by coupling CDK- and ATM-mediated phosphorylation of CtIP through modulating the interaction of CtIP with Nbs1, which significantly helps to understand how DSB repair is regulated in mammalian cells to maintain genome stability.

Published
2013

4. CtIP Protein Dimerization Is Critical for Its Recruitment to Chromosomal DNA Double-stranded Breaks*

Author

Wang, Hailong, Shao, Zhengping, Shi, Linda Z, Hwang, Patty Yi-Hwa, Truong, Lan N, Berns, Michael W, Chen, David J, and Wu, Xiaohua

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Rare Diseases, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Generic health relevance, Cancer, Amino Acid Motifs, BRCA1 Protein, Carrier Proteins, Cell Cycle Proteins, Cell Line, Chromosomes, Human, DNA Breaks, Double-Stranded, DNA Repair, Endodeoxyribonucleases, Homologous Recombination, Humans, Mutation, Nuclear Proteins, Phosphorylation, Protein Multimerization, Protein Structure, Tertiary, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

CtIP (CtBP-interacting protein) associates with BRCA1 and the Mre11-Rad50-Nbs1 (MRN) complex and plays an essential role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair. It has been described that CtIP forms dimers in mammalian cells, but the biological significance is not clear. In this study, we identified a conserved motif in the N terminus of CtIP, which is required for dimer formation. We further showed that CtIP mutants impaired in forming dimers are strongly defective in HR, end resection, and activation of the ataxia telangiectasia and Rad3-related pathway, without notable change of CtIP interactions with BRCA1 or Nbs1. In addition to HR, CtIP dimerization is also required for microhomology-mediated end joining. Live cell imaging of enhanced GFP-tagged CtIP demonstrates that the CtIP dimerization mutant fails to be localized to DSBs, whereas placing a heterologous dimerization motif to the dimerization mutant restores CtIP recruitment to DSBs. These studies suggest that CtIP dimer formation is essential for its recruitment to DSBs on chromatin upon DNA damage. Furthermore, DNA damage-induced phosphorylation of CtIP is significantly reduced in the CtIP dimerization mutants. Therefore, in addition to the C-terminal conserved domains critical for CtIP function, the dimerization motif on the N terminus of CtIP is also conserved and essential for its function in DNA damage responses. The severe repair defects of CtIP dimerization mutants are likely due to the failure in localization to chromosomal DSBs upon DNA damage.

Published
2012

19. Cell Cycle Dependence of DNA-dependent Protein Kinase Phosphorylation in Response to DNA Double Strand Breaks*

Author

Chen, Benjamin PC, Chan, Doug W, Kobayashi, Junya, Burma, Sandeep, Asaithamby, Aroumougame, Morotomi-Yano, Keiko, Botvinick, Elliot, Qin, Jun, and Chen, David J

Subjects
Genetics, Amino Acid Sequence, Cell Cycle, Cell Line, Cell Line, Tumor, Cell Nucleus, DNA Damage, DNA Repair, DNA-Activated Protein Kinase, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Genetic Vectors, HeLa Cells, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Nuclear Proteins, Phosphorylation, Protein Serine-Threonine Kinases, Radiation, Ionizing, S Phase, Serine, Threonine, Hela Cells, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

DNA-dependent protein kinase (DNA-PK), consisting of Ku and DNA-PKcs subunits, is the key component of the non-homologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair. Although the kinase activity of DNA-PKcs is essential for NHEJ, thus far, no in vivo substrate has been conclusively identified except for an autophosphorylation site on DNA-PKcs itself (threonine 2609). Here we report the ionizing radiation (IR)-induced autophosphorylation of DNA-PKcs at a novel site, serine 2056, the phosphorylation of which is required for the repair of DSBs by NHEJ. Interestingly, IR-induced DNA-PKcs autophosphorylation is regulated in a cell cycle-dependent manner with attenuated phosphorylation in the S phase. In contrast, DNA replication-associated DSBs resulted in DNA-PKcs autophosphorylation and localization to DNA damage sites. These results indicate that although IR-induced DNA-PKcs phosphorylation is attenuated in the S phase, DNA-PKcs is preferentially activated by the physiologically relevant DNA replication-associated DSBs at the sites of DNA synthesis.

Published
2005

43. Data from A Human Breast Cell Model of Preinvasive to Invasive Transition

Author

Rizki, Aylin, primary, Weaver, Valerie M., primary, Lee, Sun-Young, primary, Rozenberg, Gabriela I., primary, Chin, Koei, primary, Myers, Connie A., primary, Bascom, Jamie L., primary, Mott, Joni D., primary, Semeiks, Jeremy R., primary, Grate, Leslie R., primary, Mian, I. Saira, primary, Borowsky, Alexander D., primary, Jensen, Roy A., primary, Idowu, Michael O., primary, Chen, Fanqing, primary, Chen, David J., primary, Petersen, Ole W., primary, Gray, Joe W., primary, and Bissell, Mina J., primary

Published
2023
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46. Supplementary Figures 1-3 from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

Author

Al Rashid, Shahnaz T., primary, Dellaire, Graham, primary, Cuddihy, Andrew, primary, Jalali, Farid, primary, Vaid, Mita, primary, Coackley, Carla, primary, Folkard, Melvyn, primary, Xu, Yang, primary, Chen, Benjamin P.C., primary, Chen, David J., primary, Lilge, Lothar, primary, Prise, Kevin M., primary, Bazett Jones, David P., primary, and Bristow, Robert G., primary

Published
2023
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48. Data from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

Author

Al Rashid, Shahnaz T., primary, Dellaire, Graham, primary, Cuddihy, Andrew, primary, Jalali, Farid, primary, Vaid, Mita, primary, Coackley, Carla, primary, Folkard, Melvyn, primary, Xu, Yang, primary, Chen, Benjamin P.C., primary, Chen, David J., primary, Lilge, Lothar, primary, Prise, Kevin M., primary, Bazett Jones, David P., primary, and Bristow, Robert G., primary

Published
2023
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49. Supplementary Figure Legends from Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo

Author

Al Rashid, Shahnaz T., primary, Dellaire, Graham, primary, Cuddihy, Andrew, primary, Jalali, Farid, primary, Vaid, Mita, primary, Coackley, Carla, primary, Folkard, Melvyn, primary, Xu, Yang, primary, Chen, Benjamin P.C., primary, Chen, David J., primary, Lilge, Lothar, primary, Prise, Kevin M., primary, Bazett Jones, David P., primary, and Bristow, Robert G., primary

Published
2023
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