E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells.
BRCA1 Protein
/ deficiency
BRCA2 Protein
/ deficiency
Cell Cycle
Cell Line, Tumor
Cell Survival
/ genetics
DNA Damage
/ drug effects
DNA Helicases
/ genetics
DNA Repair
/ genetics
DNA Replication
/ drug effects
Humans
Hydroxyurea
/ pharmacology
MRE11 Homologue Protein
/ deficiency
Mutation
Phosphorylation
RNA, Small Interfering
Rad51 Recombinase
/ metabolism
Replication Protein A
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
/ genetics
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
23
08
2019
revised:
15
01
2020
accepted:
03
03
2020
entrez:
12
5
2020
pubmed:
12
5
2020
medline:
20
3
2021
Statut:
ppublish
Résumé
BRCA1/2 help maintain genomic integrity by stabilizing stalled forks. Here, we identify the E3 ligase RFWD3 as an essential modulator of stalled fork stability in BRCA2-deficient cells and show that codepletion of RFWD3 rescues fork degradation, collapse, and cell sensitivity upon replication stress. Stalled forks in BRCA2-deficient cells accumulate phosphorylated and ubiquitinated replication protein A (ubq-pRPA), the latter of which is mediated by RFWD3. Generation of this intermediate requires SMARCAL1, suggesting that it depends on stalled fork reversal. We show that in BRCA2-deficient cells, rescuing fork degradation might not be sufficient to ensure fork repair. Depleting MRE11 in BRCA2-deficient cells does block fork degradation, but it does not prevent fork collapse and cell sensitivity in the presence of replication stress. No such ubq-pRPA intermediate is formed in BRCA1-deficient cells, and our results suggest that BRCA1 may function upstream of BRCA2 in the stalled fork repair pathway. Collectively, our data uncover a novel mechanism by which RFWD3 destabilizes forks in BRCA2-deficient cells.
Identifiants
pubmed: 32391871
pii: 151752
doi: 10.1083/jcb.201908192
pmc: PMC7265328
pii:
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
MRE11 protein, human
0
RNA, Small Interfering
0
Replication Protein A
0
RFWD3 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Rad51 Recombinase
EC 2.7.7.-
SMARCAL1 protein, human
EC 2.7.7.-
MRE11 Homologue Protein
EC 3.1.-
DNA Helicases
EC 3.6.4.-
Hydroxyurea
X6Q56QN5QC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020 Duan et al.
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