Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress
Copyright policy )Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress
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.
- University of Oxford United Kingdom
- CRUK/MRC Oxford Institute for Radiation Oncology United Kingdom
- Cancer Research UK United Kingdom
- Universities UK United Kingdom
- University of Alabama at Birmingham United States
Proteasome Endopeptidase Complex, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Genome Integrity, Repair and Replication, Protein Serine-Threonine Kinases, Cullin Proteins, DNA-Binding Proteins, Mice, Oxidative Stress, Phosphotransferases (Alcohol Group Acceptor), DNA Repair Enzymes, Enzyme Stability, Animals, Humans, Phosphorylation, Carrier Proteins, DNA Damage, HeLa Cells
Proteasome Endopeptidase Complex, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Genome Integrity, Repair and Replication, Protein Serine-Threonine Kinases, Cullin Proteins, DNA-Binding Proteins, Mice, Oxidative Stress, Phosphotransferases (Alcohol Group Acceptor), DNA Repair Enzymes, Enzyme Stability, Animals, Humans, Phosphorylation, Carrier Proteins, DNA Damage, HeLa Cells
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