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

Pfister, Sophia X., Ahrabi, Sara, Zalmas, Lykourgos-Panagiotis , Sarkar, Sovan, Aymard, François, Bachrati, Csanad, Helleday, Thomas, Legube, Gaëlle, LaThangue, Nicholas B., Porter, Angrew C. G. and Humphrey, Timothy C. (2014) SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Reports, 7 (6). pp. 2006-2018. ISSN 2211-1247

Full content URL: http://dx.doi.org/10.1016/j.celrep.2014.05.026

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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. © 2014 The Authors.

Additional Information:Open Access funded by Medical Research Council
Keywords:Cellular processes, Histone modification, Homologous recombination repair, Double-strand break resection, Microhomology-mediated end-joining, JCOpen
Subjects:C Biological Sciences > C130 Cell Biology
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Life Sciences
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ID Code:14490
Deposited On:15 Jul 2014 15:36

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