title: PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair.
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.
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Hanan
authors.initials: H
authors.lastname: Khoury-Haddad
authors.forename: Noga
authors.initials: N
authors.lastname: Guttmann-Raviv
authors.forename: Inbal
authors.initials: I
authors.lastname: Ipenberg
authors.forename: David
authors.initials: D
authors.lastname: Huggins
authors.forename: Anand D
authors.initials: AD
authors.lastname: Jeyasekharan
authors.forename: Nabieh
authors.initials: N
authors.lastname: Ayoub
mesh_terms: D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D007834:Lasers; D008164:Luminescent Proteins / Q000378:metabolism; D008852:Microradiography; D018613:Microscopy, Confocal; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D056484:Jumonji Domain-Containing Histone Demethylases; D008164:Luminescent Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011965:Receptors, Glucocorticoid; D000097573:Red Fluorescent Protein; C521694:KDM4D protein, human; C499320:PARP1 protein, human
keywords: PARylation; chromosome instability; histone demethylation