TY - JOUR
T1 - SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability
AU - Hjorth-Jensen, Kim
AU - Maya-Mendoza, Apolinar
AU - Dalgaard, Nanna
AU - Sigurðsson, Jón O
AU - Bartek, Jiri
AU - Iglesias-Gato, Diego
AU - Olsen, Jesper V.
AU - Flores-Morales, Amilcar
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1093/nar/gky719
DO - 10.1093/nar/gky719
M3 - Journal article
C2 - 30124983
VL - 46
SP - 9484
EP - 9495
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 18
ER -