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. © 2012 The Author(s).
  • 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