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 2017-10-19 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. application/pdf https://n2t.net/ark:/12658/srd1319052 https://susi.usi.ch/global/documents/319052 https://susi.usi.ch/documents/319052/files/taglialatela_mol-cell.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molcel.2017.09.036 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319052 info:eu-repo/semantics/openAccess License undefined Molecular Cell. - 2017, vol. 68, no. 2, p. 414-430.e8 DNA replication stress Replication fork instability Replication fork reversal BRCA1 and BRCA2 RAD51 SMARCAL1 ZRANB3 HLTF MRE11 Breast and ovarian cancer info:eu-repo/classification/udc/57/59 Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers http://purl.org/coar/resource_type/c_6501