Sequential role of RAD51 paralog complexes in replication fork remodeling and restart

Matteo Berti, Federico Teloni, Sofija Mijic, Sebastian Ursich, Jevgenij Fuchs, Maria Dilia Palumbieri, Jana Krietsch, Jonas A. Schmid, Edwige B. Garcin, Stéphanie Gon, Mauro Modesti, Matthias Altmeyer () and Massimo Lopes ()
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Matteo Berti: University of Zurich
Federico Teloni: University of Zurich
Sofija Mijic: University of Zurich
Sebastian Ursich: University of Zurich
Jevgenij Fuchs: University of Zurich
Maria Dilia Palumbieri: University of Zurich
Jana Krietsch: University of Zurich
Jonas A. Schmid: University of Zurich
Edwige B. Garcin: Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université
Stéphanie Gon: Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université
Mauro Modesti: Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université
Matthias Altmeyer: University of Zurich
Massimo Lopes: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Homologous recombination (HR) factors were recently implicated in DNA replication fork remodeling and protection. While maintaining genome stability, HR-mediated fork remodeling promotes cancer chemoresistance, by as-yet elusive mechanisms. Five HR cofactors – the RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 – recently emerged as crucial tumor suppressors. Albeit extensively characterized in DNA repair, their role in replication has not been addressed systematically. Here, we identify all RAD51 paralogs while screening for modulators of RAD51 recombinase upon replication stress. Single-molecule analysis of fork progression and architecture in isogenic cellular systems shows that the BCDX2 subcomplex restrains fork progression upon stress, promoting fork reversal. Accordingly, BCDX2 primes unscheduled degradation of reversed forks in BRCA2-defective cells, boosting genomic instability. Conversely, the CX3 subcomplex is dispensable for fork reversal, but mediates efficient restart of reversed forks. We propose that RAD51 paralogs sequentially orchestrate clinically relevant transactions at replication forks, cooperatively promoting fork remodeling and restart.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17324-z

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DOI: 10.1038/s41467-020-17324-z

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