Replication fork reversal triggers fork degradation in BRCA2-defective cells

Sofija Mijic, Ralph Zellweger, Nagaraja Chappidi, Matteo Berti, Kurt Jacobs, Karun Mutreja, Sebastian Ursich, Arnab Ray Chaudhuri, Andre Nussenzweig, Pavel Janscak and Massimo Lopes ()
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Sofija Mijic: University of Zurich
Ralph Zellweger: University of Zurich
Nagaraja Chappidi: University of Zurich
Matteo Berti: University of Zurich
Kurt Jacobs: University of Zurich
Karun Mutreja: University of Zurich
Sebastian Ursich: University of Zurich
Arnab Ray Chaudhuri: National Institutes of Health
Andre Nussenzweig: National Institutes of Health
Pavel Janscak: University of Zurich
Massimo Lopes: University of Zurich

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01164-5

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