ATR Signaling Uncouples the Role of RAD51 Paralogs in Homologous Recombination and Replication Stress Response.
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Cell Survival
/ drug effects
DNA Breaks, Double-Stranded
DNA Repair
DNA Replication
DNA-Binding Proteins
/ antagonists & inhibitors
Genomic Instability
Homologous Recombination
Humans
Hydroxyurea
/ pharmacology
Morpholines
/ pharmacology
Mutagenesis, Site-Directed
Phosphorylation
Pyrones
/ pharmacology
RNA Interference
RNA, Small Interfering
/ metabolism
Rad51 Recombinase
/ genetics
Signal Transduction
ATM/ATR
RAD51 paralogs
fork collapse
fork stability
homologous recombination
replication stress response
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
19
02
2019
revised:
31
07
2019
accepted:
04
09
2019
entrez:
17
10
2019
pubmed:
17
10
2019
medline:
19
8
2020
Statut:
ppublish
Résumé
ATR kinase-mediated replication checkpoint is vital for genome maintenance following replication stress. Previously, we showed that XRCC2-RAD51D (DX2) sub-complex of RAD51 paralogs restrains active DNA synthesis during dNTP alterations, in a manner dependent on ATR-mediated phosphorylation of XRCC2. Here, we find that unrestrained fork progression in XRCC2 deficiency and phosphorylation defect causes replication-associated errors, subsequently resulting in genome-wide double-strand breaks (DSBs) and early activation of ATM signaling. Cells defective in XRCC2 phosphorylation exhibit ATM/ATR-mediated early activation of XRCC3 during perturbed replication, which facilitates recombination-mediated repair of the post-replicative DNA damage and thereby promotes cell viability. Collectively, our findings identify collaborative roles of RAD51 paralog complexes during replication stress and reveal their differential regulation by ATR signaling to promote cell survival and genome integrity.
Identifiants
pubmed: 31618626
pii: S2211-1247(19)31185-4
doi: 10.1016/j.celrep.2019.09.008
pii:
doi:
Substances chimiques
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
0
DNA-Binding Proteins
0
Morpholines
0
Pyrones
0
RNA, Small Interfering
0
X-ray repair cross complementing protein 3
0
XRCC2 protein, human
0
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Hydroxyurea
X6Q56QN5QC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
551-559.e4Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.