SPOP mutation leads to genomic instability in prostate cancer
- Weill Cornell Medical College, United Kingdom
- Weill Cornell Medical College, United States
- University of Trento, Italy
- Institute of Cancer Research, United Kingdom
Abstract
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.
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Animal experimentation: All protocols were performed with prior approval of the WCMC IACUC under protocol 2012-0065.
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© 2015, Boysen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SPOP mutation leads to genomic instability in prostate cancer
eLife 4:e09207.
https://doi.org/10.7554/eLife.09207
