Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress.

Academic Article

Abstract

  • 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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    Keywords

  • 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
  • Digital Object Identifier (doi)

    Author List

  • Parsons JL; Khoronenkova SV; Dianova II; Ternette N; Kessler BM; Datta PK; Dianov GL
  • Start Page

  • 11404
  • End Page

  • 11415
  • Volume

  • 40
  • Issue

  • 22