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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.

Original publication




Journal article


Nucleic Acids Res

Publication Date





11404 - 11415


Animals, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Cell Cycle Proteins, Cullin Proteins, DNA Damage, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Stability, HeLa Cells, Humans, Mice, Oxidative Stress, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination