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.
Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers / A. Taglialatela, S. Alvarez, G. Leuzzi, V. Sannino, L. Ranjha, J. Huang, C. Madubata, R. Anand, B. Levy, R. Rabadan, P. Cejka, V. Costanzo, A. Ciccia. - In: MOLECULAR CELL. - ISSN 1097-2765. - 68:2(2017 Oct 19), pp. 414-430.
|Titolo:||Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers|
COSTANZO, VINCENZO (Penultimo) [Supervision]
|Parole Chiave:||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 Helicases; DNA-Binding Proteins; Genomic Instability; Humans; MRE11 Homologue Protein; Transcription Factors; Ubiquitin-Protein Ligases; DNA Breaks|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||19-ott-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.molcel.2017.09.036|
|Appare nelle tipologie:||01 - Articolo su periodico|