CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress

• DOI: 10.1016/j.molcel.2018.09.014
• Publication Date: 2018-10-18T10:49:49Z
• Authors: Sara Przetocka; Antonio Porro; Hella A. Bolck; Christina Walker; Aleksandra Lezaja; Anika Trenner; Christine von Aesch; Sarah-Felicitas H...; Alan D. D’Andrea; Raphael Ceccaldi; Matthias Altmeyer; Alessandro A. Sar...
• Keywords: DNA Replication; 0301 basic medicine; DNA Repair; fork protection; homologous recombination; Genomic Instability; Cell Line; 1307 Cell Biology; 03 medical and health sciences; DNA2; 1312 Molecular Biology; Humans; DNA Breaks, Double-Stranded; Homologous Recombination; Molecular Biology; BRCA2 Protein; MRE11 Homologue Protein; Deoxyribonucleases; Endodeoxyribonucleases; BRCA1 Protein; 10061 Institute of Molecular Cancer Research; MRE11; DNA Helicases; Nuclear Proteins; Cell Biology; BRCA1; 10226 Department of Molecular Mechanisms of Disease; BRCA2; DNA replication stress; DNA-Binding Proteins; CtIP; 570 Life sciences; biology; Carrier Proteins; genome stability; synthetic lethaility; Protein Binding

Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.