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

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 - 2018/10/12

Y1 - 2018/10/12

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

SN - 0305-1048

VL - 46

SP - 9484

EP - 9495

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 18

ER -