2017-12-01
Replication fork reversal triggers fork degradation in BRCA2-defective cells
Publication
Publication
Nature Communications , Volume 8 - Issue 1
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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| doi.org/10.1038/s41467-017-01164-5, hdl.handle.net/1765/102522 | |
| Nature Communications | |
| Organisation | Erasmus MC: University Medical Center Rotterdam |
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Mijic, S. (Sofija), Zellweger, R. (Ralph), Chappidi, N. (Nagaraja), Berti, M. (Matteo), Jacobs, K. (Kurt), Mutreja, K. (Karun), … Lopes, M. (Massimo). (2017). Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nature Communications, 8(1). doi:10.1038/s41467-017-01164-5 |
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