Sequential role of RAD51 paralog complexes in replication fork remodeling and restart.
BRCA2 Protein
/ metabolism
Cell Line, Tumor
Chromosome Structures
/ metabolism
Chromosomes
/ ultrastructure
DNA Damage
DNA Repair
DNA Replication
DNA-Binding Proteins
/ metabolism
Genomic Instability
Homologous Recombination
Humans
Microscopy
Mutagens
Mutation
Osteosarcoma
/ metabolism
RNA, Small Interfering
/ metabolism
Rad51 Recombinase
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 07 2020
15 07 2020
Historique:
received:
14
10
2019
accepted:
16
06
2020
entrez:
17
7
2020
pubmed:
17
7
2020
medline:
9
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32669601
doi: 10.1038/s41467-020-17324-z
pii: 10.1038/s41467-020-17324-z
pmc: PMC7363682
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
DNA-Binding Proteins
0
Mutagens
0
RAD51B protein, human
0
RAD51C protein, human
0
RAD51D protein, human
0
RNA, Small Interfering
0
X-ray repair cross complementing protein 3
0
XRCC2 protein, human
0
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3531Subventions
Organisme : European Research Council
ID : 714326
Pays : International
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