期刊
NUCLEIC ACIDS RESEARCH
卷 40, 期 22, 页码 11404-11415出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks909
关键词
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资金
- Medical Research Council
- Cancer Research UK
- Biomedical Research Centre (NIHR), Oxford, UK
- National Institute of Health/National Cancer Institute
- Veterans Administration
- Medical Research Council [MC_PC_12002, MC_U142762994, G0501068] Funding Source: researchfish
- MRC [MC_PC_12002, G0501068, MC_U142762994] Funding Source: UKRI
We examined the mechanism regulating the cellular levels of PNKP, the major kinase/phosphatase involved in the repair of oxidative DNA damage, and find that it is controlled by ATM phosphorylation and ubiquitylation-dependent proteasomal degradation. We discovered that ATM-dependent phosphorylation of PNKP at serines 114 and 126 in response to oxidative DNA damage inhibits ubiquitylation-dependent proteasomal degradation of PNKP, and consequently increases PNKP stability that is required for DNA repair. We have also purified a novel Cul4A-DDB1 ubiquitin ligase complex responsible for PNKP ubiquitylation and identify serine-threonine kinase receptor associated protein (STRAP) as the adaptor protein that provides specificity of the complex to PNKP. Strap(-/-) mouse embryonic fibroblasts subsequently contain elevated cellular levels of PNKP, and show elevated resistance to oxidative DNA damage. These data demonstrate an important role for ATM and the Cul4A-DDB1-STRAP ubiquitin ligase in the regulation of the cellular levels of PNKP, and consequently in the repair of oxidative DNA damage.
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