35 results on '"RNA demethylation"'
Search Results
2. Genome-Wide Identification of the Soybean AlkB Homologue Gene Family and Functional Characterization of GmALKBH10Bs as RNA m 6 A Demethylases and Expression Patterns under Abiotic Stress.
- Author
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Zhao, Jie, Yang, Tengfeng, Liu, Peng, Liu, Huijie, Zhang, Hui, Guo, Sichao, Liu, Xiaoye, Chen, Xiaoguang, and Chen, Mingjia
- Subjects
GENE expression ,GENE families ,ABIOTIC stress ,CHROMOSOME duplication ,PLANT development - Abstract
Soybean (Glycine max (L.) Merr) is one of the most important crops worldwide, but its yield is vulnerable to abiotic stresses. In Arabidopsis, the AlkB homologue (ALKBH) family genes plays a crucial role in plant development and stress response. However, the identification and functions of its homologous genes in soybean remain obscured. Here, we identified a total of 22 ALKBH genes in soybean and classified them into seven subfamilies according to phylogenetic analysis. Gene duplication events among the family members and gene structure, conserved domains, and motifs of all candidate genes were analyzed. By comparing the changes in the m
6 A levels on mRNA from hair roots between soybean seedlings harboring the empty vector and those harboring the GmALKBH10B protein, we demonstrated that all four GmALKBH10B proteins are bona fide m6 A RNA demethylases in vivo. Subcellular localization and expression patterns of the GmALKBH10B revealed that they might be functionally redundant. Furthermore, an analysis of cis-elements coupled with gene expression data demonstrated that GmALKBH10B subfamily genes, including GmALKBH10B1, GmALKBH10B2, GmALKBH10B3, and GmALKBH10B4, are likely involved in the cis-elements' response to various environmental stimuli. In summary, our study is the first to report the genome-wide identification of GmALKBH family genes in soybean and to determine the function of GmALKBH10B proteins as m6 A RNA demethylases, providing insights into GmALKBH10B genes in response to abiotic stresses. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
- Full Text
- View/download PDF
Catalog
3. The biological function of demethylase ALKBH1 and its role in human diseases
- Author
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Jing Zhong, Zhengyang Xu, Ning Ding, Yanting Wang, and Wenwen Chen
- Subjects
ALKBH1 ,RNA demethylation ,DNA demethylation ,Cancer ,N1-methyladenosine ,N6-methyladenine ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
AlkB homolog 1 (ALKBH1) is a member of the AlkB family of dioxygenases that are dependent on Fe(II) and α-ketoglutarate. Mounting evidence demonstrates that ALKBH1 exhibits enzymatic activity against various substrates, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), N3-methylcytidine (m3C), 5-methylcytosine (m5C), N6-methyladenine (N6-mA, 6mA), and H2A, indicating its dual roles in different biological processes and involvement in human diseases. Up to the present, there is ongoing debate regarding ALKBH1's enzymatic activity. In this review, we present a comprehensive summary of recent research on ALKBH1, including its substrate diversity and pathological roles in a wide range of human disorders, the underlying mechanisms of its functions, and its dysregulation. We also explored the potential of ALKBH1 as a prognostic target. more...
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- 2024
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4. Genome-Wide Identification of the Soybean AlkB Homologue Gene Family and Functional Characterization of GmALKBH10Bs as RNA m6A Demethylases and Expression Patterns under Abiotic Stress
- Author
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Jie Zhao, Tengfeng Yang, Peng Liu, Huijie Liu, Hui Zhang, Sichao Guo, Xiaoye Liu, Xiaoguang Chen, and Mingjia Chen
- Subjects
AlkB homologue ,m6A ,RNA demethylation ,soybean ,abiotic stress ,Botany ,QK1-989 - Abstract
Soybean (Glycine max (L.) Merr) is one of the most important crops worldwide, but its yield is vulnerable to abiotic stresses. In Arabidopsis, the AlkB homologue (ALKBH) family genes plays a crucial role in plant development and stress response. However, the identification and functions of its homologous genes in soybean remain obscured. Here, we identified a total of 22 ALKBH genes in soybean and classified them into seven subfamilies according to phylogenetic analysis. Gene duplication events among the family members and gene structure, conserved domains, and motifs of all candidate genes were analyzed. By comparing the changes in the m6A levels on mRNA from hair roots between soybean seedlings harboring the empty vector and those harboring the GmALKBH10B protein, we demonstrated that all four GmALKBH10B proteins are bona fide m6A RNA demethylases in vivo. Subcellular localization and expression patterns of the GmALKBH10B revealed that they might be functionally redundant. Furthermore, an analysis of cis-elements coupled with gene expression data demonstrated that GmALKBH10B subfamily genes, including GmALKBH10B1, GmALKBH10B2, GmALKBH10B3, and GmALKBH10B4, are likely involved in the cis-elements’ response to various environmental stimuli. In summary, our study is the first to report the genome-wide identification of GmALKBH family genes in soybean and to determine the function of GmALKBH10B proteins as m6A RNA demethylases, providing insights into GmALKBH10B genes in response to abiotic stresses. more...
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- 2024
- Full Text
- View/download PDF
5. The role of demethylase AlkB homologs in cancer.
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Qiao Li and Qingsan Zhu
- Subjects
DIOXYGENASES ,DEMETHYLASE ,GENETIC regulation ,DNA methylation ,DNA replication ,DEMETHYLATION - Abstract
The AlkB family (ALKBH1-8 and FTO), a member of the Fe (II)- and aketoglutarate-dependent dioxygenase superfamily, has shown the ability to catalyze the demethylation of a variety of substrates, including DNA, RNA, and histones. Methylation is one of the natural organisms' most prevalent forms of epigenetic modifications. Methylation and demethylation processes on genetic material regulate gene transcription and expression. A wide variety of enzymes are involved in these processes. The methylation levels of DNA, RNA, and histones are highly conserved. Stable methylation levels at different stages can coordinate the regulation of gene expression, DNA repair, and DNA replication. Dynamic methylation changes are essential for the abilities of cell growth, differentiation, and division. In some malignancies, the methylation of DNA, RNA, and histones is frequently altered. To date, nine AlkB homologs as demethylases have been identified in numerous cancers' biological processes. In this review, we summarize the latest advances in the research of the structures, enzymatic activities, and substrates of the AlkB homologs and the role of these nine homologs as demethylases in cancer genesis, progression, metastasis, and invasion. We provide some new directions for the AlkB homologs in cancer research. In addition, the AlkB family is expected to be a new target for tumor diagnosis and treatment. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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6. Detailed resume of RNA m6A demethylases
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Dandan Shen, Bo Wang, Ya Gao, Lijuan Zhao, Yaping Bi, Jinge Zhang, Ning Wang, Huiqin Kang, Jingru Pang, Ying Liu, Luping Pang, Zhe-Sheng Chen, Yi-Chao Zheng, and Hong-Min Liu
- Subjects
FTO ,ALKBH5 ,RNA demethylation ,Diseases ,Inhibitors ,Screening ,Therapeutics. Pharmacology ,RM1-950 - Abstract
N6-Methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m6A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m6A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5. more...
- Published
- 2022
- Full Text
- View/download PDF
7. Tet2 modulates M2 macrophage polarization via mRNA 5-methylcytosine in allergic rhinitis.
- Author
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Fan, Wenjun, Liu, Peiqiang, Tan, Lu, Lv, Hao, Zhou, Huiqin, Tao, Zezhang, and Xu, Yu
- Subjects
- *
REGULATORY T cells , *RNA modification & restriction , *GENE expression , *ALLERGIC rhinitis , *AUTOREGRESSIVE models , *NASAL mucosa - Abstract
• M2 macrophage polarization is linked to type 2 inflammation and allergic severity. • Tet2 regulates 5-methylcytosine (m5C) oxidation in mRNA, similar to its function in DNA, highlighting a new regulatory mechanism. • Tet2 alleviates allergic severity and M2 polarization. • Tet2 deficiency reduces mRNA m5C demethylation of Klf4 and Rock1, promoting M2 polarization in allergies, offering new protective insights. Allergic rhinitis (AR) represents a hallmark of obvious hypersensitivity with an imbalance of immune responses, including abnormal macrophage activity in local tissues. It has been reported that alternatively activated macrophages (M2) may contribute to allergic pathogenesis. Ten-eleven translocation (Tet) enzymes can oxidize 5-methylcytosine (m5C) in mRNA, implying the epigenetic regulation of post-transcriptional RNA modification. Our previous study suggested that decreased Tet2 impairs the function of regulatory T cells, failing to exert a protective role in AR. However, the mechanism of Tet2 in macrophage polarization has been little discussed. In this paper, we investigate the regulatory role of Tet2 in macrophage polarization under allergic inflammation. Macrophage immunofluorescence and eosinophil counts were used to confirm the inflammatory and polarized state in the nasal mucosa of AR patients. Additionally, we used Raw264.7 cells to explore the relationships among mRNA methylation, Tet2 expression, and the macrophage polarization process. Furthermore an Ovalbumin (OVA)-mediated AR mouse model was established with wild-type (WT) and Tet2 gene knockout (Tet2−/−) mice to verify the role of Tet2 in AR severity and macrophage polarization. The final stage comprised RNA sequencing, methylated RNA immunoprecipitation with qPCR (MeRIP-qPCR) using bone marrow-derived macrophages (BMDMs) from WT and Tet2−/− mice to explore the effect of Tet2 deficiency on the mRNA methylation level of M2-related genes under OVA treatment. A two-tailed Student's t -test was used to compare two groups, and Spearman correlation analysis was applied for relationship analysis. M2-macrophages were confirmed as the dominant subtype associated with eosinophil levels in AR nasal tissues. In vitro analyses demonstrated that mRNA methylation and Tet2 are linked to M2 macrophages. Additionally, we found that Tet2 influences local allergic severity and macrophage polarization. Specifically, Tet2 deficiency decreased the mRNA m5C demethylation levels of Klf4 and Rock1, contributing to M2 polarization in an allergic state. The findings of this study demonstrate that Tet2 may play a protective role in AR by negatively regulating M2-related factors through mRNA m5C demethylation. These findings provide new insights into AR therapy, suggesting that intervening in macrophage polarization at the post-transcriptional level could be a novel therapeutic strategy. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
8. ALKBH9C, a potential RNA m6A demethylase, regulates the response of Arabidopsis to abiotic stresses and abscisic acid.
- Author
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Amara, Umme, Shoaib, Yasira, and Kang, Hunseung
- Subjects
- *
ABSCISIC acid , *ABIOTIC stress , *DEMETHYLASE , *DROUGHT tolerance , *RNA , *ARABIDOPSIS , *GERMINATION - Abstract
Although several studies have shown that AlkB homolog (ALKBH) proteins are potential RNA demethylases (referred to as 'erasers'), biological functions of only a few ALKBH proteins have been characterized to date. In this study, we determined the function of ALKBH9C (At4g36090) in seed germination and seedling growth of Arabidopsis thaliana in response to abiotic stress and abscisic acid (ABA). Seed germination of the alkbh9c mutant was delayed in response to salt, drought, cold and ABA. Moreover, seedling growth of the mutant was repressed under salt stress or ABA but enhanced under drought conditions. Notably, the stress‐responsive phenotypes were associated with the altered expression of several m6A‐modified transcripts related to salt, drought or ABA response. Global m6A levels were increased in the alkbh9c mutant, and ALKBH9C bound to m6A‐modified RNAs and had in vitro m6A demethylase activity, suggesting its potential role as an m6A eraser. The m6A levels in several stress‐responsive genes were increased in the alkbh9c mutant, and the stability of m6A‐modified transcripts was altered in the mutant. Collectively, our results suggest that m6A eraser ALKBH9C is crucial for seed germination and seedling growth of Arabidopsis in response to abiotic stresses or ABA via affecting the stability of stress‐responsive transcripts. Summary statement: Addition and removal of methylation marks in RNAs is critical for the response of plants to abiotic stresses and abscisic acid. In this study, we show that ALKBH9C is a potential m6A demethylase that plays a crucial role in seed germination and seedling growth of Arabidopsis in response to salt stress, drought stress, and abscisic acid. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
- Full Text
- View/download PDF
9. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential
- Author
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Jianwei Qu, Haimeng Yan, Yifan Hou, Wen Cao, Yang Liu, Enfan Zhang, Jingsong He, and Zhen Cai
- Subjects
m6A modification ,ALKBH5 ,RNA demethylation ,Cancer ,Gene regulation ,Therapeutic target ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract RNA demethylase ALKBH5 takes part in the modulation of N6-methyladenosine (m6A) modification and controls various cell processes. ALKBH5-mediated m6A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m6A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies. more...
- Published
- 2022
- Full Text
- View/download PDF
10. Detailed resume of RNA m6A demethylases.
- Author
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Shen, Dandan, Wang, Bo, Gao, Ya, Zhao, Lijuan, Bi, Yaping, Zhang, Jinge, Wang, Ning, Kang, Huiqin, Pang, Jingru, Liu, Ying, Pang, Luping, Chen, Zhe-Sheng, Zheng, Yi-Chao, and Liu, Hong-Min
- Subjects
RNA ,ADIPOSE tissues ,MEDICAL screening ,MESSENGER RNA ,DEMETHYLATION - Abstract
N 6-Methyladenosine (m
6 A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m6 A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m6 A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5. This review systematically describes the chemical and biological functions of RNA demethylases FTO and ALKBH5, from their crystal structure to inhibitors development and screening, demethylation mechanism and substrates to biological functions and roles in diseases. [Display omitted] [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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11. Role of the m 6 A demethylase ALKBH5 in gastrointestinal tract cancer (Review).
- Author
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Zhang L, Jing M, Song Q, Ouyang Y, Pang Y, Ye X, Fu Y, and Yan W
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- Humans, Gene Expression Regulation, Neoplastic, Adenosine metabolism, Adenosine analogs & derivatives, Animals, Biomarkers, Tumor metabolism, Biomarkers, Tumor genetics, AlkB Homolog 5, RNA Demethylase metabolism, AlkB Homolog 5, RNA Demethylase genetics, Gastrointestinal Neoplasms genetics, Gastrointestinal Neoplasms metabolism, Gastrointestinal Neoplasms pathology
- Abstract
N6‑methyladenosine (m
6 A) is one of the most universal, abundant and conserved types of internal post‑transcriptional modifications in eukaryotic RNA, and is involved in nuclear RNA export, RNA splicing, mRNA stability, gene expression, microRNA biogenesis and long non‑coding RNA metabolism. AlkB homologue 5 (ALKBH5) acts as a m6A demethylase to regulate a wide variety of biological processes closely associated with tumour progression, tumour metastasis, tumour immunity and tumour drug resistance. ALKBH5 serves a crucial role in human digestive system tumours, mainly through post‑transcriptional regulation of m6 A modification. The present review discusses progress in the study of the m6A demethylase ALKBH5 in gastrointestinal tract cancer, summarizes the potential molecular mechanisms of ALKBH5 dysregulation in gastrointestinal tract cancer, and discusses the significance of ALKBH5‑targeted therapy, which may provide novel ideas for future clinical prognosis prediction, biomarker identification and precise treatment. more...- Published
- 2025
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12. High-Throughput Small RNA Sequencing Enhanced by AlkB-Facilitated RNA de-Methylation (ARM-Seq)
- Author
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Hrabeta-Robinson, Eva, Marcus, Erin, Cozen, Aaron E, Phizicky, Eric M, and Lowe, Todd M
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,AlkB Enzymes ,Animals ,Gene Library ,High-Throughput Nucleotide Sequencing ,Humans ,Methylation ,RNA ,RNA ,Transfer ,Sequence Analysis ,RNA ,RNA Sequencing ,Transfer RNA ,AlkB ,RNA demethylation ,N-1-methyladenosine (m(1)A) ,N-3-methylcytidine (m(3)C) ,N-1-methylguanosine (m(1)G) ,N 1-methyladenosine ,N 1-methylguanosine ,N 3-methylcytidine ,Other Chemical Sciences ,Biochemistry and Cell Biology ,Developmental Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
N 1-methyladenosine (m1A), N 3-methylcytidine (m3C), and N 1-methylguanosine (m1G) are common in transfer RNA (tRNA) and tRNA-derived fragments. These modifications alter Watson-Crick base-pairing, and cause pauses or stops during reverse transcription required for most high-throughput RNA sequencing protocols, resulting in inefficient detection of methyl-modified RNAs. Here, we describe a procedure to demethylate RNAs containing m1A, m3C, or m1G using the Escherichia coli dealkylating enzyme AlkB, along with instructions for subsequent processing with widely used protocols for small RNA sequencing. more...
- Published
- 2017
13. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.
- Author
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Qu, Jianwei, Yan, Haimeng, Hou, Yifan, Cao, Wen, Liu, Yang, Zhang, Enfan, He, Jingsong, and Cai, Zhen
- Subjects
- *
RNA metabolism , *DEMETHYLASE , *RNA , *NON-coding RNA , *GENE expression - Abstract
RNA demethylase ALKBH5 takes part in the modulation of N6-methyladenosine (m6A) modification and controls various cell processes. ALKBH5-mediated m6A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m6A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
- Full Text
- View/download PDF
14. Reaction-mediated dual signaling inhibition gated organic photoelectrochemical transistors biosensor for FTO activity detection based on the in situ oxidization of ZnSe/Bi2MoO6 heterojunction.
- Author
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Zhang, Miao, Zhou, Yunlei, Zhang, Haowei, Yin, Huanshun, Yu, Zhengkun, Yin, Zhidong, Tian, Ying, Wang, Minghui, and Ai, Shiyun
- Subjects
- *
TRANSISTORS , *HETEROJUNCTIONS , *ELECTRON donors , *BIOSENSORS , *NUCLEOTIDE sequence , *ADIPOSE tissues , *CONJUGATED polymers , *POLYMERS - Abstract
[Display omitted] • Hydroquinone-mediated OPECT biosensing strategy was developed. • ZnSe/Bi 2 MoO 6 heterojunction was employed as photoactive material. • Sensitive and selective detection of FTO protein was achieved. • Hemin catalyzed the oxidation of ZnSe and hydroquinone by H 2 O 2 was employed to achieve signal suppression. • Rhein and perfluorohexane sulfonate inhibited FTO protein activity. Organic photoelectrochemical transistor (OPECT) biosensing is a new concept that combines photoelectrochemical and organic electrochemical transistor biosensing. It reduces background noise and combines both signal amplification for low abundance biomolecule detection. In this work, an OPECT biosensor for the detection of fat mass and obesity-associated protein (FTO) was constructed, in which ZnSe/Bi 2 MoO 6 was chosen as the gate material, hm6ARNA (containing N6-methyladenine RNA sequence) as the target molecule, and hydroquinone as the electron donor. Under FTO oxidation induced RNA demethylation, the formation of hemin loaded with G-quadruplex on the electrode surface was triggered. With the catalysis of hemin-based DNAzyme towards the oxidation reaction caused by H 2 O 2 towards hydroquinone and ZnSe, the electron donor was consumed and ZnSe was oxidized in situ to form SeO 2 which reduced the photo-anodic response. The variation of the gate effectively gated the state of the channel polymer thus producing different channel current responses, a process that was closely related to the content of FTO. In addition, the effects of rhein and potassium perfluorohexanesulfonate on FTO activity were also investigated in this experiment, with IC 50 values of 10.62 μM, 31.28 mg/L respectively. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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15. Identification of Flavin Mononucleotide as a Cell‐Active Artificial N6‐Methyladenosine RNA Demethylase.
- Author
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Xie, Li‐Jun, Yang, Xiao‐Ti, Wang, Rui‐Li, Cheng, Hou‐Ping, Li, Zhi‐Yan, Liu, Li, Mao, Lanqun, Wang, Ming, and Cheng, Liang
- Subjects
- *
FLAVIN mononucleotide , *DEMETHYLASE , *RNA , *SMALL molecules , *NON-coding RNA , *DIOXYGENASES - Abstract
N6‐Methyladenosine (m6A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6A residues in mRNA. Herein, the first identification of a small‐molecule modulator that functions as an artificial m6A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology. Take Me away: Flavin mononucleotide (FMN) was identified as an effective artificial N6‐methyladenosine (m6A) demethylase when combined with blue‐light irradiation, and functions similarly to natural demethylating enzymes like FTO and ALKBH5. This is the first example of a small molecule that can directly act on the cellular levels of the m6A modification in genomic RNA. [ABSTRACT FROM AUTHOR] more...
- Published
- 2019
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16. ALKBH10B-mediated m6A demethylation is crucial for drought tolerance by affecting mRNA stability in Arabidopsis.
- Author
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Han, Rongpeng, Shoaib, Yasira, Cai, Jing, and Kang, Hunseung
- Subjects
- *
DROUGHT tolerance , *DEMETHYLATION , *DROUGHT management , *MESSENGER RNA , *ARABIDOPSIS thaliana , *ABSCISIC acid - Abstract
N6-methyladenosine (m6A) is the most abundant modification found in eukaryotic mRNAs. The methyltransferases ("writers") and demethylases ("erasers") add and remove m6A marks, respectively, which controls transcriptome-wide m6A levels and plays crucial roles in plant development and response to environmental cues. The alpha-ketoglutarate-dependent dioxygenase homolog 10 (ALKBH10) is the first confirmed plant m6A eraser and is involved in floral transition in Arabidopsis (Arabidopsis thaliana). Recent studies showed that ALKBH10B is also involved in the Arabidopsis response to salt, drought or ABA. However, the molecular mechanism underlying the ALKBH10B-guided drought tolerance has not yet been explored. In this study, we investigated how ALKBH10B-mediated m6A demethylation confers drought tolerance in Arabidopsis. The alkbh10b mutants were sensitive to drought stress, whereas the ALKBH10B-overexpressing plants were tolerant to drought stress. Notably, under dehydration stress, the m6A levels of several drought stress positive effectors were elevated in the alkbh10b mutants, and their transcript abundance was lower in the mutants but higher in the transgenic lines. Importantly, the decay rates of these m6A-modified transcripts were significantly higher in the alkbh10b relative to the wild-type under dehydration stress. Collectively, these findings establish a molecular link between ALKBH10B-guided m6A demethylation and mRNA stability control in drought stress tolerance. • The m6A eraser alkbh10b mutants were sensitive to drought stress. • The m6A levels of several m6A-modified transcripts involved in the drought stress response were elevated in the alkbh10b mutants. • The decay rates of m6A-modified transcripts were higher in the alkbh10b mutant than in the wild type under dehydration stress. • These findings establish a molecular link between ALKBH10B-mediated m6A demethylation and drought stress tolerance. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
- Full Text
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17. The role of demethylase AlkB homologs in cancer.
- Author
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Li Q and Zhu Q
- Abstract
The AlkB family (ALKBH1-8 and FTO), a member of the Fe (II)- and α-ketoglutarate-dependent dioxygenase superfamily, has shown the ability to catalyze the demethylation of a variety of substrates, including DNA, RNA, and histones. Methylation is one of the natural organisms' most prevalent forms of epigenetic modifications. Methylation and demethylation processes on genetic material regulate gene transcription and expression. A wide variety of enzymes are involved in these processes. The methylation levels of DNA, RNA, and histones are highly conserved. Stable methylation levels at different stages can coordinate the regulation of gene expression, DNA repair, and DNA replication. Dynamic methylation changes are essential for the abilities of cell growth, differentiation, and division. In some malignancies, the methylation of DNA, RNA, and histones is frequently altered. To date, nine AlkB homologs as demethylases have been identified in numerous cancers' biological processes. In this review, we summarize the latest advances in the research of the structures, enzymatic activities, and substrates of the AlkB homologs and the role of these nine homologs as demethylases in cancer genesis, progression, metastasis, and invasion. We provide some new directions for the AlkB homologs in cancer research. In addition, the AlkB family is expected to be a new target for tumor diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li and Zhu.) more...
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- 2023
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18. Base-resolution quantitative DAMM-seq for mapping RNA methylations in tRNA and mitochondrial polycistronic RNA.
- Author
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Zhang LS, Ju CW, Jiang B, and He C
- Subjects
- Humans, Methylation, RNA, Mitochondrial genetics, RNA, Mitochondrial metabolism, RNA chemistry, AlkB Homolog 5, RNA Demethylase chemistry, AlkB Homolog 5, RNA Demethylase metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO chemistry, Alpha-Ketoglutarate-Dependent Dioxygenase FTO metabolism, RNA Precursors, RNA, Transfer metabolism
- Abstract
The human AlkB family proteins, such as FTO and ALKBH5, are known to mediate RNA m
6 A demethylation. However, although ALKBH7 localizes in mitochondria and affects metabolism, the detailed biological function and mechanism have remained unknown for years. We developed Demethylation-Assisted Multiple Methylation sequencing (DAMM-seq) to simultaneously detect N1 -methyladenosine (m1 A), N3 -methylcytidine (m3 C), N1 -methylguanosine (m1 G) and N2 ,N2 -dimethylguanosine (m2 2 G) methylations in both steady-state RNA and nascent RNA, and discovered that human ALKBH7 demethylates m2 2 G and m1 A within mt-Ile and mt-Leu1 pre-tRNA regions, respectively, in mitochondrial polycistronic RNA. DAMM-seq quantitatively and sensitively monitors the methylation stoichiometry change at pre-tRNA junctions within nascent mt-RNA, revealing the target region where ALKBH7 regulates RNA processing and local structural switch of polycistronic mt-RNAs. A new RNA demethylase in human cells was characterized through the base-resolution quantification of multiple RNA methylations in nascent mt-RNA, resolving the long-standing question about the functional substrate of ALKBH7., (Copyright © 2023. Published by Elsevier Inc.) more...- Published
- 2023
- Full Text
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19. Therapeutic potential of ALKB homologs for cardiovascular disease
- Author
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Yuan-Yuan Cheng, Jiaming Liu, Mingzhu Xiao, Keng-Yu Chen, Zhongqiu Liu, and Cui-Ling Xian
- Subjects
0301 basic medicine ,DNA Repair ,DNA damage ,Inflammation ,RM1-950 ,Biology ,medicine.disease_cause ,Protein Structure, Secondary ,03 medical and health sciences ,0302 clinical medicine ,Drug Delivery Systems ,Histone demethylation ,medicine ,ALKB homologs ,Animals ,Humans ,Demethylation ,Pharmacology ,Genetics ,Autophagy ,AlkB Enzymes ,RNA ,General Medicine ,DNA Methylation ,RNA demethylation ,030104 developmental biology ,DNA demethylation ,Cardiovascular diseases ,Oxidative stress ,030220 oncology & carcinogenesis ,Therapy ,Therapeutics. Pharmacology ,medicine.symptom ,DNA Damage - Abstract
Cardiovascular diseases (CVDs) are the leading causes of human death. Recently, ALKB homologs, including ALKBH1-8 and FTO, have been found to have a variety of biological functions, such as histone demethylation, RNA demethylation, and DNA demethylation. These functions may regulate the physiological and pathological processes of CVDs, including inflammation, oxidative stress, cell apoptosis, and mitochondrial, endothelial, and fat metabolism dysfunction. In the present review, we summarize the biological functions of ALKB homologs and the relationship between the ALKB homologs and CVDs. Importantly, we discuss the roles of ALKB homologs in the regulation of oxidative stress, inflammation, autophagy, and DNA damage in CVDs, as well as the practical applications of ALKB homologs inhibitors or agonists in treating CVDs. In conclusion, the ALKBH family might be a promising target for CVDs therapy. more...
- Published
- 2020
20. Functional Characterization of a Putative RNA Demethylase ALKBH6 in
- Author
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Trinh Thi, Huong, Le Nguyen Tieu, Ngoc, and Hunseung, Kang
- Subjects
abiotic stress ,Arabidopsis Proteins ,AlkB Enzymes ,Arabidopsis ,food and beverages ,Down-Regulation ,Germination ,Sodium Chloride ,Plant Roots ,Article ,Droughts ,RNA demethylation ,Plant Growth Regulators ,Gene Expression Regulation, Plant ,Seedlings ,Stress, Physiological ,Mutation ,Seeds ,RNA methylation ,RNA ,ALKBH ,epitranscriptomics ,Abscisic Acid ,Signal Transduction - Abstract
RNA methylation and demethylation, which is mediated by RNA methyltransferases (referred to as “writers”) and demethylases (referred to as “erasers”), respectively, are emerging as a key regulatory process in plant development and stress responses. Although several studies have shown that AlkB homolog (ALKBH) proteins are potential RNA demethylases, the function of most ALKBHs is yet to be determined. The Arabidopsis thaliana genome contains thirteen genes encoding ALKBH proteins, the functions of which are largely unknown. In this study, we characterized the function of a potential eraser protein, ALKBH6 (At4g20350), during seed germination and seedling growth in Arabidopsis under abiotic stresses. The seeds of T-DNA insertion alkbh6 knockdown mutants germinated faster than the wild-type seeds under cold, salt, or abscisic acid (ABA) treatment conditions but not under dehydration stress conditions. Although no differences in seedling and root growth were observed between the alkbh6 mutant and wild-type under normal conditions, the alkbh6 mutant showed a much lower survival rate than the wild-type under salt, drought, or heat stress. Cotyledon greening of the alkbh6 mutants was much higher than that of the wild-type upon ABA application. Moreover, the transcript levels of ABA signaling-related genes, including ABI3 and ABI4, were down-regulated in the alkbh6 mutant compared to wild-type plants. Importantly, the ALKBH6 protein had an ability to bind to both m6A-labeled and m5C-labeled RNAs. Collectively, these results indicate that the potential eraser ALKBH6 plays important roles in seed germination, seedling growth, and survival of Arabidopsis under abiotic stresses. more...
- Published
- 2020
21. Functional Characterization of a Putative RNA Demethylase ALKBH6 in Arabidopsis Growth and Abiotic Stress Responses
- Author
-
Hunseung Kang, Le Nguyen Tieu Ngoc, and Trinh Thi Huong
- Subjects
0106 biological sciences ,0301 basic medicine ,abiotic stress ,Mutant ,Arabidopsis ,Biology ,01 natural sciences ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Arabidopsis thaliana ,Physical and Theoretical Chemistry ,Molecular Biology ,Gene ,Abscisic acid ,lcsh:QH301-705.5 ,Spectroscopy ,Abiotic stress ,Organic Chemistry ,RNA ,food and beverages ,General Medicine ,biology.organism_classification ,Computer Science Applications ,Cell biology ,RNA demethylation ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,RNA methylation ,Demethylase ,ALKBH ,epitranscriptomics ,010606 plant biology & botany - Abstract
RNA methylation and demethylation, which is mediated by RNA methyltransferases (referred to as &ldquo, writers&rdquo, ) and demethylases (referred to as &ldquo, erasers&rdquo, ), respectively, are emerging as a key regulatory process in plant development and stress responses. Although several studies have shown that AlkB homolog (ALKBH) proteins are potential RNA demethylases, the function of most ALKBHs is yet to be determined. The Arabidopsis thaliana genome contains thirteen genes encoding ALKBH proteins, the functions of which are largely unknown. In this study, we characterized the function of a potential eraser protein, ALKBH6 (At4g20350), during seed germination and seedling growth in Arabidopsis under abiotic stresses. The seeds of T-DNA insertion alkbh6 knockdown mutants germinated faster than the wild-type seeds under cold, salt, or abscisic acid (ABA) treatment conditions but not under dehydration stress conditions. Although no differences in seedling and root growth were observed between the alkbh6 mutant and wild-type under normal conditions, the alkbh6 mutant showed a much lower survival rate than the wild-type under salt, drought, or heat stress. Cotyledon greening of the alkbh6 mutants was much higher than that of the wild-type upon ABA application. Moreover, the transcript levels of ABA signaling-related genes, including ABI3 and ABI4, were down-regulated in the alkbh6 mutant compared to wild-type plants. Importantly, the ALKBH6 protein had an ability to bind to both m6A-labeled and m5C-labeled RNAs. Collectively, these results indicate that the potential eraser ALKBH6 plays important roles in seed germination, seedling growth, and survival of Arabidopsis under abiotic stresses. more...
- Published
- 2020
22. NAIL‐MS in E. coli Determines the Source and Fate of Methylation in tRNA
- Author
-
Verena Weber, Stefanie Kellner, and Valentin F. Reichle
- Subjects
0301 basic medicine ,Methylation ,Biochemistry ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,RNA, Transfer ,Very Important Paper ,In vivo ,Escherichia coli ,isotopic labeling ,tRNA ,Molecular Biology ,Demethylation ,TRNA methylation ,Full Paper ,Nitrogen Isotopes ,Chemistry ,Organic Chemistry ,RNA ,Full Papers ,Deuterium ,RNA demethylation ,Methyl methanesulfonate ,030104 developmental biology ,Isotope Labeling ,Transfer RNA ,Nucleic acid ,Molecular Medicine ,Ribonucleosides ,nucleosides - Abstract
In all domains of life, the nucleobases of tRNA can be methylated. These methylations are introduced either by enzymes or by the reaction of methylating agents with the nucleophilic centers of the nucleobases. Herein, we present a systematic approach to identify the methylation sites within RNA in vitro and in vivo. For discrimination between enzymatic tRNA methylation and tRNA methylation damage in bacteria, we used nucleic acid isotope labeling coupled mass spectrometry (NAIL‐MS). With NAIL‐MS, we clearly observed the formation of 7‐methylguanosine, 3‐methyluridine, and 6‐methyladenosine during exposure of bacteria to the alkylating agent methyl methanesulfonate (MMS) in vivo. These damage products were not reported to form in tRNA in vivo, as they were masked by the enzymatically formed modified nucleosides in previous studies. In addition, we found formation of the known damage products 1‐methyladenosine and 3‐methylcytidine in vivo. With a dynamic NAIL‐MS setup, we observed tRNA repair by demethylation of these two RNA modifications in vivo. Furthermore, we saw the potential repair of 6‐methyladenosine but not 7‐methylguanosine in bacterial tRNA. more...
- Published
- 2018
- Full Text
- View/download PDF
23. YTH Domain: A Family of N6-methyladenosine (m6A) Readers
- Author
-
Chao Xu, Shanhui Liao, and Hongbin Sun
- Subjects
0301 basic medicine ,YT521-B homology ,Adenosine ,RNA methylation ,Computational biology ,Review ,Biochemistry ,Homology (biology) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein Domains ,RNA modification ,Genetics ,Animals ,Humans ,Molecular Biology ,lcsh:QH301-705.5 ,Methyltransferase complex ,RNA ,Epitranscriptome ,RNA-Binding Proteins ,RNA demethylation ,Computational Mathematics ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,RNA splicing ,Signal transduction ,DNA ,Protein Binding - Abstract
Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N6-methyladenosine (m6A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m6A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m6A modification is reversible and dynamic. Moreover, m6A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6A recognition by YTH domain-containing proteins, which would shed new light on m6A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications. Keywords: RNA modification, RNA methylation, RNA demethylation, YT521-B homology, Epitranscriptome more...
- Published
- 2018
24. FTO, RNA epigenetics and epilepsy.
- Author
-
Rowles, Joie, Wong, Morgan, Powers, Ryan, and Olsen, Mark
- Published
- 2012
- Full Text
- View/download PDF
25. Detailed resume of RNA m 6 A demethylases.
- Author
-
Shen D, Wang B, Gao Y, Zhao L, Bi Y, Zhang J, Wang N, Kang H, Pang J, Liu Y, Pang L, Chen ZS, Zheng YC, and Liu HM
- Abstract
N 6-Methyladenosine (m
6 A) is the most abundant internal modification in eukaryotic mRNA, playing critical role in various bioprocesses. Like other epigenetic modifications, m6 A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m6 A demethylases have been reported, fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.) more...- Published
- 2022
- Full Text
- View/download PDF
26. Ascorbic Acid in Epigenetic Reprogramming.
- Author
-
Liu X, Khan A, Li H, Wang S, Chen X, and Huang H
- Subjects
- Antioxidants, Cellular Reprogramming genetics, DNA Methylation genetics, Ascorbic Acid pharmacology, Epigenesis, Genetic
- Abstract
Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms primarily due to its cofactor role in Fe(II) and 2-oxoglutarate-dependent dioxygenases, including the DNA demethylases Ten Eleven Translocase (TET) and histone demethylases. Epigenetic variations have been shown to play a critical role in somatic cell reprogramming. DNA methylation and histone methylation are extensively recognized as barriers to somatic cell reprogramming. N6-methyladenosine (m6A), known as RNA methylation, is an epigenetic modification of mRNAs and has also been shown to play a role in regulating cellular reprogramming. Multiple cofactors are reported to promote the activity of these demethylases, including vitamin C. Therefore, this review focuses and examines the evidence and mechanism of vitamin C in DNA and histone demethylation and highlights its potential involvement in the regulation of m6A demethylation. It also shows the significant contribution of vitamin C in epigenetic regulation, and the affiliation of demethylases with vitamin C-facilitated epigenetic reprogramming., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) more...
- Published
- 2022
- Full Text
- View/download PDF
27. Therapeutic potential of ALKB homologs for cardiovascular disease.
- Author
-
Xiao, Ming-Zhu, Liu, Jia-Ming, Xian, Cui-Ling, Chen, Keng-Yu, Liu, Zhong-Qiu, and Cheng, Yuan-Yuan
- Subjects
- *
CARDIOVASCULAR diseases , *DNA demethylation , *OXIDATIVE stress , *DNA damage , *BIOMARKERS - Abstract
• ALKB homologs can regulate the physiological and pathological processes of CVDs. • ALKBH1, ALKBH8 and FTO are associated with the process of oxidative stress and inflammation in CVDs. • ALKBH1 might be a potential biomarker for AS, and developing its inhibitors can be benefit to AS therapy. • FTO agonist may be able to improve MI-induced heart failure. • ALKBH family might be a promising target for CVDs therapy. Cardiovascular diseases (CVDs) are the leading causes of human death. Recently, ALKB homologs, including ALKBH1−8 and FTO, have been found to have a variety of biological functions, such as histone demethylation, RNA demethylation, and DNA demethylation. These functions may regulate the physiological and pathological processes of CVDs, including inflammation, oxidative stress, cell apoptosis, and mitochondrial, endothelial, and fat metabolism dysfunction. In the present review, we summarize the biological functions of ALKB homologs and the relationship between the ALKB homologs and CVDs. Importantly, we discuss the roles of ALKB homologs in the regulation of oxidative stress, inflammation, autophagy, and DNA damage in CVDs, as well as the practical applications of ALKB homologs inhibitors or agonists in treating CVDs. In conclusion, the ALKBH family might be a promising target for CVDs therapy. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
- Full Text
- View/download PDF
28. Functional Characterization of a Putative RNA Demethylase ALKBH6 in Arabidopsis Growth and Abiotic Stress Responses.
- Author
-
Huong, Trinh Thi, Ngoc, Le Nguyen Tieu, and Kang, Hunseung
- Subjects
- *
ABIOTIC stress , *GERMINATION , *DEMETHYLASE , *RNA , *RNA methylation , *ARABIDOPSIS , *ROOT growth - Abstract
RNA methylation and demethylation, which is mediated by RNA methyltransferases (referred to as "writers") and demethylases (referred to as "erasers"), respectively, are emerging as a key regulatory process in plant development and stress responses. Although several studies have shown that AlkB homolog (ALKBH) proteins are potential RNA demethylases, the function of most ALKBHs is yet to be determined. The Arabidopsis thaliana genome contains thirteen genes encoding ALKBH proteins, the functions of which are largely unknown. In this study, we characterized the function of a potential eraser protein, ALKBH6 (At4g20350), during seed germination and seedling growth in Arabidopsis under abiotic stresses. The seeds of T-DNA insertion alkbh6 knockdown mutants germinated faster than the wild-type seeds under cold, salt, or abscisic acid (ABA) treatment conditions but not under dehydration stress conditions. Although no differences in seedling and root growth were observed between the alkbh6 mutant and wild-type under normal conditions, the alkbh6 mutant showed a much lower survival rate than the wild-type under salt, drought, or heat stress. Cotyledon greening of the alkbh6 mutants was much higher than that of the wild-type upon ABA application. Moreover, the transcript levels of ABA signaling-related genes, including ABI3 and ABI4, were down-regulated in the alkbh6 mutant compared to wild-type plants. Importantly, the ALKBH6 protein had an ability to bind to both m6A-labeled and m5C-labeled RNAs. Collectively, these results indicate that the potential eraser ALKBH6 plays important roles in seed germination, seedling growth, and survival of Arabidopsis under abiotic stresses. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
- Full Text
- View/download PDF
29. High-Throughput Small RNA Sequencing Enhanced by AlkB-Facilitated RNA de-Methylation (ARM-Seq)
- Author
-
Todd M. Lowe, Eva Hrabeta-Robinson, Aaron E. Cozen, Eric M. Phizicky, and Erin Marcus
- Subjects
0301 basic medicine ,030103 biophysics ,Small RNA ,N 1-methylguanosine ,AlkB ,RNA-dependent RNA polymerase ,Computational biology ,Methylation ,N 3-methylcytidine ,Article ,03 medical and health sciences ,RNA, Transfer ,N-1-methyladenosine (m(1)A) ,RNA polymerase I ,Genetics ,Animals ,Humans ,N-1-methylguanosine (m(1)G) ,Gene Library ,RNA Sequencing ,N 1-methyladenosine ,biology ,Chemistry ,Sequence Analysis, RNA ,AlkB Enzymes ,RNA ,High-Throughput Nucleotide Sequencing ,Nuclease protection assay ,RNA demethylation ,Transfer ,030104 developmental biology ,RNA editing ,biology.protein ,Biochemistry and Cell Biology ,Transfer RNA ,RIP-Chip ,Other Chemical Sciences ,Sequence Analysis ,N-3-methylcytidine (m(3)C) ,Developmental Biology - Abstract
N 1-methyladenosine (m1A), N 3-methylcytidine (m3C), and N 1-methylguanosine (m1G) are common in transfer RNA (tRNA) and tRNA-derived fragments. These modifications alter Watson-Crick base-pairing, and cause pauses or stops during reverse transcription required for most high-throughput RNA sequencing protocols, resulting in inefficient detection of methyl-modified RNAs. Here, we describe a procedure to demethylate RNAs containing m1A, m3C, or m1G using the Escherichia coli dealkylating enzyme AlkB, along with instructions for subsequent processing with widely used protocols for small RNA sequencing. more...
- Published
- 2017
30. Identification of Flavin Mononucleotide as a Cell-Active Artificial N 6 -Methyladenosine RNA Demethylase.
- Author
-
Xie LJ, Yang XT, Wang RL, Cheng HP, Li ZY, Liu L, Mao L, Wang M, and Cheng L
- Subjects
- Adenosine chemistry, Adenosine metabolism, AlkB Homolog 5, RNA Demethylase analysis, Alpha-Ketoglutarate-Dependent Dioxygenase FTO analysis, Flavin Mononucleotide analysis, HEK293 Cells, HeLa Cells, Humans, Molecular Structure, Adenosine analogs & derivatives, AlkB Homolog 5, RNA Demethylase metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO metabolism, Flavin Mononucleotide metabolism
- Abstract
N
6 -Methyladenosine (m6 A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6 A residues in mRNA. Herein, the first identification of a small-molecule modulator that functions as an artificial m6 A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6 A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6 A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...- Published
- 2019
- Full Text
- View/download PDF
31. FTO, RNA epigenetics and epilepsy
- Author
-
Ryan Powers, Joie Rowles, Mark Olsen, and Morgan Wong
- Subjects
Central Nervous System ,Cancer Research ,Adenosine ,RNA methylation ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Biology ,Methylation ,Epigenesis, Genetic ,RNA epigenetics ,Transcriptome ,chemistry.chemical_compound ,microRNA ,Humans ,Epigenetics ,RNA, Messenger ,RNA Processing, Post-Transcriptional ,Molecular Biology ,3' Untranslated Regions ,Point of View ,Genetics ,Epilepsy ,N6-methyladenosine ,RNA ,Proteins ,RNA demethylation ,RNA silencing ,MicroRNAs ,chemistry ,Gene Expression Regulation ,RNA splicing ,N6-Methyladenosine ,FTO - Abstract
Several recent landmark papers describing N(6) -methyladenosine (m(6) A) RNA modifications have provided valuable new insights as to the importance of m(6) A in the RNA transcriptome and in furthering the understanding of RNA epigenetics. One endogenous enzyme responsible for demethylating RNA m(6) A, FTO, is highly expressed in the CNS and is likely involved in mRNA metabolism, splicing or other nuclear RNA processing events. microRNAs (miRNAs), a family of small, non-coding transcripts that bind to target mRNAs and inhibit subsequent translation, are highly expressed in the CNS and are associated with several neurological disorders, including epilepsy. miRNAs frequently bind to recognition sequences in the 3'UTR, a region that is also enriched for m(6) A. Certain specific miRNAs are upregulated by neuronal activity and are coupled to epileptogenesis; these miRNAs contain a consensus m(6) A site that if methylated could possibly regulate miRNA processing or function. This commentary highlights aspects from recent papers to propose a functional association between FTO, RNA epigenetics and epilepsy. more...
- Published
- 2012
32. NAIL-MS in E. coli Determines the Source and Fate of Methylation in tRNA.
- Author
-
Reichle VF, Weber V, and Kellner S
- Subjects
- Deuterium, Isotope Labeling methods, Mass Spectrometry methods, Methylation, Nitrogen Isotopes, Ribonucleosides chemistry, Escherichia coli genetics, RNA, Transfer chemistry
- Abstract
In all domains of life, the nucleobases of tRNA can be methylated. These methylations are introduced either by enzymes or by the reaction of methylating agents with the nucleophilic centers of the nucleobases. Herein, we present a systematic approach to identify the methylation sites within RNA in vitro and in vivo. For discrimination between enzymatic tRNA methylation and tRNA methylation damage in bacteria, we used nucleic acid isotope labeling coupled mass spectrometry (NAIL-MS). With NAIL-MS, we clearly observed the formation of 7-methylguanosine, 3-methyluridine, and 6-methyladenosine during exposure of bacteria to the alkylating agent methyl methanesulfonate (MMS) in vivo. These damage products were not reported to form in tRNA in vivo, as they were masked by the enzymatically formed modified nucleosides in previous studies. In addition, we found formation of the known damage products 1-methyladenosine and 3-methylcytidine in vivo. With a dynamic NAIL-MS setup, we observed tRNA repair by demethylation of these two RNA modifications in vivo. Furthermore, we saw the potential repair of 6-methyladenosine but not 7-methylguanosine in bacterial tRNA., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.) more...
- Published
- 2018
- Full Text
- View/download PDF
33. YTH Domain: A Family of N 6 -methyladenosine (m 6 A) Readers.
- Author
-
Liao S, Sun H, and Xu C
- Subjects
- Adenosine chemistry, Adenosine metabolism, Animals, Humans, Protein Binding, Protein Domains, RNA chemistry, RNA metabolism, RNA-Binding Proteins metabolism, Adenosine analogs & derivatives, RNA-Binding Proteins chemistry
- Abstract
Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N
6 -methyladenosine (m6 A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m6 A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m6 A modification is reversible and dynamic. Moreover, m6 A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6 A recognition by YTH domain-containing proteins, which would shed new light on m6 A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.) more...- Published
- 2018
- Full Text
- View/download PDF
34. High-Throughput Small RNA Sequencing Enhanced by AlkB-Facilitated RNA de-Methylation (ARM-Seq).
- Author
-
Hrabeta-Robinson E, Marcus E, Cozen AE, Phizicky EM, and Lowe TM
- Subjects
- Animals, Gene Library, Humans, Methylation, RNA chemistry, RNA, Transfer chemistry, RNA, Transfer genetics, RNA, Transfer metabolism, Sequence Analysis, RNA, AlkB Enzymes metabolism, High-Throughput Nucleotide Sequencing, RNA genetics, RNA metabolism
- Abstract
N
1 -methyladenosine (m1 A), N3 -methylcytidine (m3 C), and N1pt> -methylguanosine (m 1 G) are common in transfer RNA (tRNA) and tRNA-derived fragments. These modifications alter Watson-Crick base-pairing, and cause pauses or stops during reverse transcription required for most high-throughput RNA sequencing protocols, resulting in inefficient detection of methyl-modified RNAs. Here, we describe a procedure to demethylate RNAs containing m1 A, m3 C, or m1 G using the Escherichia coli dealkylating enzyme AlkB, along with instructions for subsequent processing with widely used protocols for small RNA sequencing. more...- Published
- 2017
- Full Text
- View/download PDF
35. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond.
- Author
-
Fedeles BI, Singh V, Delaney JC, Li D, and Essigmann JM
- Subjects
- AlkB Homolog 4, Lysine Demethylase, Alkylation, DNA Damage, DNA, Single-Stranded genetics, DNA, Single-Stranded metabolism, Dioxygenases genetics, Escherichia coli enzymology, Escherichia coli genetics, Escherichia coli Proteins genetics, Gene Expression, Humans, Isoenzymes genetics, Isoenzymes metabolism, Mixed Function Oxygenases genetics, Models, Molecular, Multigene Family, Oxidation-Reduction, Substrate Specificity, DNA Repair, Dioxygenases metabolism, Escherichia coli Proteins metabolism, Iron metabolism, Ketoglutaric Acids metabolism, Mixed Function Oxygenases metabolism
- Abstract
The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli "adaptive response" protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.) more...
- Published
- 2015
- Full Text
- View/download PDF
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