期刊
ONCOGENE
卷 34, 期 46, 页码 5699-5708出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.24
关键词
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资金
- NHGRI [H3K36me3, H3K27me3]
- Cancer Research UK
- Breast Cancer Research Foundation
- Medical Research Council [G0902275, G0701935/2]
- Danish Cancer Society
- Lundbeck Foundation [R93-A8990]
- Ministry of the interior of the Czech Republic [VG20102014001]
- National Program of Sustainability [LO1304]
- Danish Council for Independent Research [DFF-1331-00262]
- NIHR RMH/ICR Biomedical Research Centre for Cancer
- EC [259303, 259892]
- UCL Overseas Research Scholarship
- European Research Council
- Prostate Cancer Foundation
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Rosetrees Trust
- MRC [G0902275, G0701935] Funding Source: UKRI
- Cancer Research UK [10748, 19310, 17786, 18377] Funding Source: researchfish
- Medical Research Council [G0701935, G0902275] Funding Source: researchfish
- Rosetrees Trust [M179] Funding Source: researchfish
- The Francis Crick Institute [10359, 10002, 10169, 10303, 10001, 10174, 10172, 10170] Funding Source: researchfish
Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase delta hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.
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