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

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Pfister SX,Ahrabi S,Zalmas LP,Sarkar S,Aymard F,Bachrati CZ,Helleday T,Legube G,La Thangue NB,Porter AC,Humphrey TC

doi

10.1016/j.celrep.2014.05.026

subject

Has Abstract

pub_date

2014-06-26 00:00:00

pages

2006-18

issue

6

issn

2211-1247

pii

S2211-1247(14)00401-X

journal_volume

7

pub_type

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