JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity

PLoS Genet. 2017 Feb 16;13(2):e1006632. doi: 10.1371/journal.pgen.1006632. eCollection 2017 Feb.

Abstract

The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination. Loss of jmjd-5 results in hypersensitivity to ionizing radiation and in meiotic defects, and it is associated with aberrant retention of RAD-51 at sites of double strand breaks. Analyses of jmjd-5 genetic interactions with genes required for resolving recombination intermediates (rtel-1) or promoting the resolution of RAD-51 double stranded DNA filaments (rfs-1 and helq-1) suggest that jmjd-5 prevents the formation of stalled postsynaptic recombination intermediates and favors RAD-51 removal. As these phenotypes are all recapitulated by a catalytically inactive jmjd-5 mutant, we propose a novel role for H3K36me2 regulation during late steps of homologous recombination critical to preserve genome integrity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Chromatin / genetics
  • DNA Damage / genetics
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Methylation / genetics
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Genomic Instability
  • Germ Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / genetics
  • Homologous Recombination / genetics*
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Protein Processing, Post-Translational / genetics
  • Rad51 Recombinase / genetics*
  • Rad51 Recombinase / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • RFS-1 protein, C elegans
  • Jumonji Domain-Containing Histone Demethylases
  • Histone-Lysine N-Methyltransferase
  • Rad51 Recombinase
  • rad-51 protein, C elegans
  • HELQ-1 protein, C elegans
  • rcq-5 protein, C elegans
  • DNA Helicases