期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 11, 页码 5601-5617出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky291
关键词
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资金
- Wellcome Trust/DBT India alliance intermediate fellowship [IA/I/13/1/500888]
- Indian Association for the Cultivation of Science intramural fund, Department of Science and Technology, Government of India
- National Cancer Institute Intramural Program, Centre for Cancer Research [Z01 BC 006150]
- National Cancer Institute, National Institutes of Health, USA
- CSIR-NET senior and junior Research Fellowship, India
Human tyrosyl-DNA phosphodiesterases (TDP) hydrolyze the phosphodiester bond between DNA and the catalytic tyrosine of Top1 to excise topoisomerase I cleavage complexes (Top1cc) that are trapped by camptothecin (CPT) and by genotoxic DNA alterations. Here we show that the protein arginine methyltransferase PRMT5 enhances the repair of Top1cc by direct binding to TDP1 and arginine dimethylation of TDP1 at residues R361 and R586. Top1-induced replication-mediated DNA damage induces TDP1 arginine methylation, enhancing its 3'-phosphodiesterase activity. TDP1 arginine methylation also increases XRCC1 association with TDP1 in response to CPT, and the recruitment of XRCC1 to Top1cc DNA damage foci. PRMT5 knockdown cells exhibit defective TDP1 activity with marked elevation in replication-coupled CPT-induced DNA damage and lethality. Finally, methylation of R361 and R586 stimulate TDP1 repair function and promote cell survival in response to CPT. Together, our findings provide evidence for the importance of PRMT5 for the post-translational regulation of TDP1 and repair of Top1cc.
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