Replication fork reversal triggers fork degradation in BRCA2-defective cells

Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2 -defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct vi...

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Vydané v:Nature communications Ročník 8; číslo 1; s. 859 - 11
Hlavní autori: Mijic, Sofija, Zellweger, Ralph, Chappidi, Nagaraja, Berti, Matteo, Jacobs, Kurt, Mutreja, Karun, Ursich, Sebastian, Ray Chaudhuri, Arnab, Nussenzweig, Andre, Janscak, Pavel, Lopes, Massimo
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 16.10.2017
Nature Publishing Group
Nature Portfolio
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631/337/1427/2190
631/337/151/2356
BRCA2 protein
BRCA2 Protein - metabolism
Breakage
Breast cancer
Cancer therapies
Carrier Proteins - metabolism
Cell cycle
Cell Line, Tumor
Chromosomal Instability
Deactivation
Degradation
Deoxyribonucleic acid
DNA
DNA Replication
Genomes
Homologous Recombination
Homology
Humanities and Social Sciences
Humans
Inactivation
Intermediates
MRE11 Homologue Protein - metabolism
MRE11 protein
multidisciplinary
Nuclear Proteins - metabolism
Rad51 Recombinase - metabolism
Rad52 DNA Repair and Recombination Protein - metabolism
Rad52 protein
Replication
Replication forks
Science
Science (multidisciplinary)
Stability
Stem cells
Tumor suppressor genes
Tumors
Visualization
ISSN:2041-1723, 2041-1723
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Shrnutí:Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2 -defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2 -defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2 -defective cells. Inactivation of these factors restores reversed fork frequency and chromosome integrity in BRCA2 -defective cells. Conversely, impairing fork reversal prevents fork degradation, but increases chromosomal breakage, uncoupling fork protection, and chromosome stability. We propose that BRCA2 is dispensable for RAD51-mediated fork reversal, but assembles stable RAD51 nucleofilaments on regressed arms, to protect them from degradation. Our data uncover the physiopathological relevance of fork reversal and illuminate a complex interplay of homologous recombination factors in fork remodeling and stability. BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-01164-5