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

Taglialatela, Angelo; Alvarez, Silvia; Leuzzi, Giuseppe; Sannino, Vincenzo; Ranjha, Lepakshi; Huang, Jen-Wei; Madubata, Chioma; Anand, Roopesh; Levy, Brynn; Rabadan, Raul; Cejka, Petr; Costanzo, Vincenzo; Ciccia, Alberto

doi:10.1016/j.molcel.2017.09.036

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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

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.

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