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ZIRC
ZFIN ID: ZDB-PUB-150917-5
SPOP mutation leads to genomic instability in prostate cancer
Boysen, G., Barbieri, C.E., Prandi, D., Blattner, M., Chae, S.S., Dahija, A., Nataraj, S., Huang, D., Marotz, C., Xu, L., Huang, J., Lecca, P., Chhangawala, S., Liu, D., Zhou, P., Sboner, A., de Bono, J.S., Demichelis, F., Houvras, Y., Rubin, M.A.
Date: 2015
Source: eLIFE   4: (Journal)
Registered Authors: Houvras, Yariv
Keywords: Cancer Genomics, DNA repair, SPOP, cell biology, human, human biology, medicine, mouse, prostate cancer, zebrafish
MeSH Terms:
  • Animals
  • Cells, Cultured
  • DNA Breaks, Double-Stranded
  • DNA Damage/drug effects
  • DNA Repair
  • Genomic Instability*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagens/metabolism
  • Nuclear Proteins/deficiency*
  • Prostatic Neoplasms/pathology*
  • Repressor Proteins/deficiency*
  • Zebrafish
PubMed: 26374986 Full text @ Elife
FIGURES
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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