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

Grant support

This work was supported by the Danish National research Foundation (DNRF82) to AES and in part by the Young Investigator Program of the Veronesi Foundation (Italy) to PGA. MB was supported by the Netherlands Organization for Scientific Research (NWO/CW) ECHO grant 711.014.005. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.