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SETD2-dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability

SETD2-dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability

Sophia X Pfister, Sara Ahrabi, Lykourgos-Panagiotis Zalmas, Sovan Sarkar, François Aymard, Csanád Z Bachrati, Thomas Helleday, Gaëlle Legube, Nicholas B La Thangue, Andrew C G Porter, Timothy C Humphrey

Cell Rep. 2014 Jun 26;7(6):2006-18.

PMID: 24931610

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416060	JMJD2A Active human			Price
IAR42416070	SETD2 active human			Price

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