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

Kim Hjorth-Jensen; Apolinar Maya-Mendoza; Nanna Dalgaard; Jón O Sigurðsson; Jiri Bartek; Diego Iglesias-Gato; Jesper V. Olsen; Amilcar Flores-Morales

doi:10.1093/nar/gky719

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

Kim Hjorth-Jensen, Apolinar Maya-Mendoza, Nanna Dalgaard, Jón O Sigurðsson, Jiri Bartek, Diego Iglesias-Gato, Jesper V. Olsen, Amilcar Flores-Morales

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Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nucleic Acids Research
Vol/bind	46
Udgave nummer	18
Sider (fra-til)	9484-9495
ISSN	0305-1048
DOI	https://doi.org/10.1093/nar/gky719
Status	Udgivet - 12 okt. 2018

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10.1093/nar/gky719

SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instabilityForlagets udgivne version, 5,75 MB

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title = "SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability",

abstract = "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.",

author = "Kim Hjorth-Jensen and Apolinar Maya-Mendoza and Nanna Dalgaard and Sigur{\dh}sson, {J{\'o}n O} and Jiri Bartek and Diego Iglesias-Gato and Olsen, {Jesper V.} and Amilcar Flores-Morales",

year = "2018",

month = oct,

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doi = "10.1093/nar/gky719",

language = "English",

volume = "46",

pages = "9484--9495",

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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 -

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

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