PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair

Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):E728-37. doi: 10.1073/pnas.1317585111. Epub 2014 Feb 3.

Abstract

Members of the lysine (K)-specific demethylase 4 (KDM4) A-D family of histone demethylases are dysregulated in several types of cancer. Here, we reveal a previously unrecognized role of KDM4D in the DNA damage response (DDR). We show that the C-terminal region of KDM4D mediates its rapid recruitment to DNA damage sites. Interestingly, this recruitment is independent of the DDR sensor ataxia telangiectasia mutated (ATM), but dependent on poly (ADP-ribose) polymerase 1 (PARP1), which ADP ribosylates KDM4D after damage. We demonstrate that KDM4D is required for efficient phosphorylation of a subset of ATM substrates. We note that KDM4D depletion impairs the DNA damage-induced association of ATM with chromatin, explaining its effect on ATM substrate phosphorylation. Consistent with an upstream role in DDR, KDM4D knockdown disrupts the damage-induced recombinase Rad51 and tumor protein P53 binding protein foci formation. Consequently, the integrity of homology-directed repair and nonhomologous end joining of DNA breaks is impaired in KDM4D-deficient cells. Altogether, our findings implicate KDM4D in DDR, furthering the links between the cancer-relevant networks of epigenetic regulation and genome stability.

Keywords: PARylation; chromosome instability; histone demethylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Breaks, Double-Stranded*
  • DNA Repair / physiology*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lasers
  • Luminescent Proteins / metabolism
  • Microradiography
  • Microscopy, Confocal
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Receptors, Glucocorticoid / metabolism
  • Red Fluorescent Protein

Substances

  • Luminescent Proteins
  • Receptors, Glucocorticoid
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4D protein, human
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases