eprintid: 10205378 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/20/53/78 datestamp: 2025-03-06 14:12:46 lastmod: 2025-03-06 14:12:46 status_changed: 2025-03-06 14:12:46 type: article metadata_visibility: show sword_depositor: 699 creators_name: Kanu, N creators_name: Groenroos, E creators_name: Martinez, P creators_name: Burrell, RA creators_name: Goh, X Yi creators_name: Bartkova, J creators_name: Maya-Mendoza, A creators_name: Mistrik, M creators_name: Rowan, AJ creators_name: Patel, H creators_name: Rabinowitz, A creators_name: East, P creators_name: Wilson, G creators_name: Santos, CR creators_name: McGranahan, N creators_name: Gulati, S creators_name: Gerlinger, M creators_name: Birkbak, NJ creators_name: Joshi, T creators_name: Alexandrov, LB creators_name: Stratton, MR creators_name: Powles, T creators_name: Matthews, N creators_name: Bates, PA creators_name: Stewart, A creators_name: Szallasi, Z creators_name: Larkin, J creators_name: Bartek, J creators_name: Swanton, C title: SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D19 divisions: G99 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 note: 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/ 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. date: 2015-11-12 date_type: published publisher: NATURE PUBLISHING GROUP official_url: https://doi.org/10.1038/onc.2015.24 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1018769 doi: 10.1038/onc.2015.24 medium: Print-Electronic pii: onc201524 lyricists_name: Swanton, Robert lyricists_name: Birkbak, Nicolai lyricists_name: McGranahan, Nicholas lyricists_name: Kanu, Nnennaya lyricists_name: Wilson, Gareth lyricists_id: CSWAN79 lyricists_id: NJBIR42 lyricists_id: NLMCG29 lyricists_id: NKANU55 lyricists_id: GWILS47 actors_name: Kanu, Nnennaya actors_id: NKANU55 actors_role: owner funding_acknowledgements: H3K36me3 [NHGRI]; H3K27me3 [NHGRI]; [Cancer Research UK]; [Breast Cancer Research Foundation]; G0902275 [Medical Research Council]; G0701935/2 [Medical Research Council]; [Danish Cancer Society]; R93-A8990 [Lundbeck Foundation]; VG20102014001 [Ministry of the interior of the Czech Republic]; LO1304 [National Program of Sustainability]; DFF-1331-00262 [Danish Council for Independent Research]; [NIHR RMH/ICR Biomedical Research Centre for Cancer]; 259303 [EC]; 259892 [EC]; [UCL Overseas Research Scholarship]; [European Research Council]; [Prostate Cancer Foundation]; [National Institute for Health Research University College London Hospitals Biomedical Research Centre]; [Rosetrees Trust]; G0902275 [MRC]; G0701935 [MRC] full_text_status: public publication: Oncogene volume: 34 number: 46 pagerange: 5699-5708 pages: 10 event_location: England issn: 0950-9232 citation: Kanu, N; Groenroos, E; Martinez, P; Burrell, RA; Goh, X Yi; Bartkova, J; Maya-Mendoza, A; ... Swanton, C; + view all <#> Kanu, N; Groenroos, E; Martinez, P; Burrell, RA; Goh, X Yi; Bartkova, J; Maya-Mendoza, A; Mistrik, M; Rowan, AJ; Patel, H; Rabinowitz, A; East, P; Wilson, G; Santos, CR; McGranahan, N; Gulati, S; Gerlinger, M; Birkbak, NJ; Joshi, T; Alexandrov, LB; Stratton, MR; Powles, T; Matthews, N; Bates, PA; Stewart, A; Szallasi, Z; Larkin, J; Bartek, J; Swanton, C; - view fewer <#> (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 <https://doi.org/10.1038/onc.2015.24>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10205378/1/Kanu%20et%20al%202015b.pdf