Journal article

Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers

  • Taglialatela, Angelo Department of Genetics and Development, Columbia University Medical Center, New York (NY), USA - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (NY), USA
  • Alvarez, Silvia Department of Genetics and Development, Columbia University Medical Center, New York (NY), USA - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (NY), USA
  • Leuzzi, Giuseppe Department of Genetics and Development, Columbia University Medical Center, New York (NY), USA - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (NY), USA
  • Sannino, Vincenzo DNA metabolism laboratory, IFOM, FIRC Institute for Molecular Oncology, Milan, Italy
  • Ranjha, Lepakshi Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Huang, Jen-Wei Department of Genetics and Development, Columbia University Medical Center, New York (NY), USA - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (NY), USA
  • Madubata, Chioma Department of Systems Biology, Columbia University Medical Center, New York (NY), USA - Department of Biomedical Informatics, Columbia University Medical Center, New York (NY), USA
  • Anand, Roopesh Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Levy, Brynn Department of Pathology and Cell Biology, Columbia University Medical Center, New York (NY), USA
  • Rabadan, Raul Department of Systems Biology, Columbia University Medical Center, New York (NY), USA - Department of Biomedical Informatics, Columbia University Medical Center, New York (NY), USA
  • Cejka, Petr Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland
  • Costanzo, Vincenzo DNA metabolism laboratory, IFOM, FIRC Institute for Molecular Oncology, Milan, Italy
  • Ciccia, Alberto Department of Genetics and Development, Columbia University Medical Center, New York (NY), USA - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York (NY), USA
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    19.10.2017
Published in:
  • Molecular Cell. - 2017, vol. 68, no. 2, p. 414-430.e8
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
  • English
Classification
Biology, life sciences
License
License undefined
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Persistent URL
https://susi.usi.ch/usi/documents/319052
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