TY  - JOUR
KW  - Science & Technology
KW  -  Life Sciences & Biomedicine
KW  -  Biochemistry & Molecular Biology
KW  -  Oncology
KW  -  Cell Biology
KW  -  Genetics & Heredity
KW  -  HOMOLOGOUS RECOMBINATION
KW  -  MUTATIONAL PROCESSES
KW  -  DAMAGE RESPONSE
KW  -  COPY NUMBER
KW  -  HISTONE
KW  -  GENE
KW  -  METHYLATION
KW  -  INSTABILITY
KW  -  FACT
KW  -  HETEROGENEITY
PB  - NATURE PUBLISHING GROUP
ID  - discovery10205378
N2  - 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 ? 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.
EP  - 5708
AV  - public
Y1  - 2015/11/12/
TI  - SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair
A1  - Kanu, N
A1  - Groenroos, E
A1  - Martinez, P
A1  - Burrell, RA
A1  - Goh, X Yi
A1  - Bartkova, J
A1  - Maya-Mendoza, A
A1  - Mistrik, M
A1  - Rowan, AJ
A1  - Patel, H
A1  - Rabinowitz, A
A1  - East, P
A1  - Wilson, G
A1  - Santos, CR
A1  - McGranahan, N
A1  - Gulati, S
A1  - Gerlinger, M
A1  - Birkbak, NJ
A1  - Joshi, T
A1  - Alexandrov, LB
A1  - Stratton, MR
A1  - Powles, T
A1  - Matthews, N
A1  - Bates, PA
A1  - Stewart, A
A1  - Szallasi, Z
A1  - Larkin, J
A1  - Bartek, J
A1  - Swanton, C
JF  - Oncogene
SN  - 0950-9232
UR  - https://doi.org/10.1038/onc.2015.24
N1  - 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/
IS  - 46
SP  - 5699
VL  - 34
ER  -