Article open access publication

SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability

Nucleic Acids Research, Oxford University Press (OUP), ISSN 0305-1048

Volume 46, 18, 2018

DOI:10.1093/nar/gky719, Dimensions: pub.1106008692, PMC: PMC6182143, PMID: 30124983,

Affiliations

Organisations

  1. (1) Danish Cancer Society, grid.417390.8
  2. (2) University of Copenhagen, grid.5254.6, KU
  3. (3) Karolinska Institute, grid.4714.6

Countries

Sweden

Denmark

Continents

Europe

Description

Mutations in SPOP, the gene most frequently point-mutated in primary prostate cancer, are associated with a high degree of genomic instability and deficiency in homologous recombination repair of DNA but the underlying mechanisms behind this defect are currently unknown. Here we demonstrate that SPOP knockdown leads to spontaneous replication stress and impaired recovery from replication fork stalling. We show that this is associated with reduced expression of several key DNA repair and replication factors including BRCA2, ATR, CHK1 and RAD51. Consequently, SPOP knockdown impairs RAD51 foci formation and activation of CHK1 in response to replication stress and compromises recovery from replication fork stalling. An SPOP interactome analysis shows that wild type (WT) SPOP but not mutant SPOP associates with multiple proteins involved in transcription, mRNA splicing and export. Consistent with the association of SPOP with transcription, splicing and RNA export complexes, the decreased expression of BRCA2, ATR, CHK1 and RAD51 occurs at the level of transcription.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

Dimensions Citation Indicators

Times Cited: 7

Field Citation Ratio (FCR): 2.29

Relative Citation ratio (RCR): 0.32

Open Access Info

Pure Gold