Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers.
- Taglialatela A Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
- Alvarez S Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
- Leuzzi G Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
- Sannino V DNA Metabolism Laboratory, IFOM, FIRC Institute for Molecular Oncology, 20139 Milan, Italy.
- Ranjha L Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
- Huang JW Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
- Madubata C Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
- Anand R Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
- Levy B Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
- Rabadan R Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA.
- Cejka P Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland; Department of Biology, Institute of Biochemistry, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
- Costanzo V DNA Metabolism Laboratory, IFOM, FIRC Institute for Molecular Oncology, 20139 Milan, Italy.
- Ciccia A Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: ac3685@cumc.columbia.edu.
- 2017-10-21
Published in:
- Molecular cell. - 2017
BRCA1 and BRCA2
DNA replication stress
HLTF
MRE11
RAD51
SMARCAL1
ZRANB3
breast and ovarian cancer
replication fork instability
replication fork reversal
BRCA2 Protein
Cell Line, Tumor
DNA Breaks
DNA Helicases
DNA-Binding Proteins
Genomic Instability
Humans
MRE11 Homologue Protein
Transcription Factors
Ubiquitin-Protein Ligases
English
To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2-deficient cells.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1016/j.molcel.2017.09.036
- PMID 29053959
- Persistent URL
- https://sonar.ch/global/documents/112393
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