CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress
| Autor: | Sara Przetocka, Christine von Aesch, Aleksandra Lezaja, Anika Trenner, Christina Walker, Hella A. Bolck, Sarah-Felicitas Himmels, Matthias Altmeyer, Antonio Porro, Alessandro A. Sartori, Alan D. D'Andrea, Raphael Ceccaldi |
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| Přispěvatelé: | University of Zurich, Sartori, Alessandro A |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genome instability DNA Repair medicine.disease_cause 1307 Cell Biology chemistry.chemical_compound DNA2 DNA Breaks Double-Stranded Homologous Recombination MRE11 Homologue Protein Deoxyribonucleases BRCA1 Protein 10061 Institute of Molecular Cancer Research MRE11 Nuclear Proteins BRCA2 Protein 10226 Department of Molecular Mechanisms of Disease DNA replication stress Cell biology DNA-Binding Proteins synthetic lethaility Protein Binding DNA Replication DNA repair fork protection Biology DNA-binding protein Genomic Instability Cell Line 03 medical and health sciences 1312 Molecular Biology medicine Humans Molecular Biology Endodeoxyribonucleases DNA Helicases DNA replication Cell Biology BRCA1 BRCA2 enzymes and coenzymes (carbohydrates) 030104 developmental biology CtIP chemistry 570 Life sciences biology Carrier Proteins Carcinogenesis Homologous recombination genome stability DNA |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2018.09.014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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