SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability

Cell Rep. 2014 Jun 26;7(6):2006-18. doi: 10.1016/j.celrep.2014.05.026. Epub 2014 Jun 12.

Abstract

Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Repair
  • Genomic Instability*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics*
  • Histones / metabolism
  • Homologous Recombination
  • Humans
  • Methylation
  • Protein Binding
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Recombinational DNA Repair*
  • Transfection

Substances

  • Histones
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, human
  • RAD51 protein, human
  • Rad51 Recombinase