Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01164-5
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Funding
- SNF [31003A_169959, 31003A_166451]
- ERC [617102]
- Swiss Cancer League grant [KFS-3967-08-2016]
- Human Frontier Science Fellowship [LT000393/2013]
- Center of Cancer Research
- US Department of Defense (BCRP DOD Idea Expansion Award) [BC133858]
- US Department of Defense (BCRP Break) [BC151331]
- Swiss National Science Foundation (SNF) [31003A_166451, 31003A_169959] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [617102] Funding Source: European Research Council (ERC)
- CDMRP [BC151331, BC133858, 793704, 893195] Funding Source: Federal RePORTER
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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.
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