期刊
CELL REPORTS
卷 7, 期 6, 页码 2006-2018出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.05.026
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类别
资金
- Medical Research Council [R066538, R19583, ANRUBT00]
- Cancer Research UK [C5255/A15935, 300/A13058]
- Clarendon Scholarship
- BBSRC [BB/H003371/1, BB/K019597/1]
- Agence Nationale pour la Recherche [ANR-09-JCJC-0138]
- Association Contre le Cancer
- Torsten and Soderberg Foundation
- BBSRC [BB/K019597/1, BB/H003371/1] Funding Source: UKRI
- MRC [G9400953, G1000807, G0500905, MC_PC_12003] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H003371/1, BB/K019597/1] Funding Source: researchfish
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [G0500905, G9400953, G1000807, MC_PC_12003] Funding Source: researchfish
- Agence Nationale de la Recherche (ANR) [ANR-09-JCJC-0138] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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