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

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

Author information

1
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
2
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
3
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse, Université Paul Sabatier, 31062 Toulouse, France; CNRS, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, 31062 Toulouse, France.
4
School of Life Sciences, University of Lincoln, Lincoln LN6 7TS, UK.
5
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
6
Gene Targeting Group, Centre for Haematology, Imperial College Faculty of Medicine, London W12 0NN, UK.
7
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: timothy.humphrey@oncology.ox.ac.uk.

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.

PMID:
24931610
PMCID:
PMC4074340
DOI:
10.1016/j.celrep.2014.05.026
[Indexed for MEDLINE]
Free PMC Article

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