期刊
ELIFE
卷 4, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.09207
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资金
- National Cancer Institute (NCI) [2R01CA125612-05A1, K08CA187417-01]
- Prostate Cancer Foundation (PCF)
- Urology Care Foundation (Urology Care Foundation, Inc.)
- New York Community Trust (NYCT) The Frederick J. and Theresa Dow Wallace Fund
- European Research Council (ERC)
- Prostate Cancer UK [PG13-036]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG13562]
- Prostate Cancer Foundation (PCF) Young Investigator Award
- Prostate Cancer UK [PG13-036] Funding Source: researchfish
Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics. DOI: 10.7554/eLife.09207.001
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