Kanu, N;
Groenroos, E;
Martinez, P;
Burrell, RA;
Goh, X Yi;
Bartkova, J;
Maya-Mendoza, A;
... Swanton, C; + view all
(2015)
SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.
Oncogene
, 34
(46)
pp. 5699-5708.
10.1038/onc.2015.24.
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Abstract
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 δ 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.
| Type: | Article |
|---|---|
| Title: | SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/onc.2015.24 |
| Publisher version: | https://doi.org/10.1038/onc.2015.24 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons AttributionNonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Oncology, Cell Biology, Genetics & Heredity, HOMOLOGOUS RECOMBINATION, MUTATIONAL PROCESSES, DAMAGE RESPONSE, COPY NUMBER, HISTONE, GENE, METHYLATION, INSTABILITY, FACT, HETEROGENEITY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205378 |
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