TY - JOUR TI - SPOP mutation leads to genomic instability in prostate cancer AU - Boysen, Gunther AU - Barbieri, Christopher E AU - Prandi, Davide AU - Blattner, Mirjam AU - Chae, Sung-Suk AU - Dahija, Arun AU - Nataraj, Srilakshmi AU - Huang, Dennis AU - Marotz, Clarisse AU - Xu, Limei AU - Huang, Julie AU - Lecca, Paola AU - Chhangawala, Sagar AU - Liu, Deli AU - Zhou, Pengbo AU - Sboner, Andrea AU - de Bono, Johann S AU - Demichelis, Francesca AU - Houvras, Yariv AU - Rubin, Mark A A2 - Espinosa, JoaquĆ­n M VL - 4 PY - 2015 DA - 2015/09/16 SP - e09207 C1 - eLife 2015;4:e09207 DO - 10.7554/eLife.09207 UR - https://doi.org/10.7554/eLife.09207 AB - 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. KW - prostate cancer KW - cancer genomic KW - SPOP KW - DNA repair JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -