Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells.
BRCA2
MiDAS
R-loops
TRCs
genome stability
mitotic DNA synthesis
transcription-replication conflicts
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
15 09 2022
15 09 2022
Historique:
received:
15
02
2022
revised:
31
05
2022
accepted:
16
07
2022
pubmed:
25
8
2022
medline:
21
9
2022
entrez:
24
8
2022
Statut:
ppublish
Résumé
Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here, we identify genome-wide the sites where MiDAS reactions occur when BRCA2 is abrogated. High-resolution profiling revealed that these sites are different from MiDAS at aphidicolin-induced common fragile sites in that they map to genomic regions replicating in the early S-phase, which are close to early-firing replication origins, are highly transcribed, and display R-loop-forming potential. Both transcription inhibition in early S-phase and RNaseH1 overexpression reduced MiDAS in BRCA2-deficient cells, indicating that transcription-replication conflicts (TRCs) and R-loops are the source of MiDAS. Importantly, the MiDAS sites identified in BRCA2-deficient cells also represent hotspots for genomic rearrangements in BRCA2-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing BRCA2 inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells.
Identifiants
pubmed: 36002001
pii: S1097-2765(22)00707-9
doi: 10.1016/j.molcel.2022.07.011
pmc: PMC9631240
pii:
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
Aphidicolin
38966-21-1
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3382-3397.e7Subventions
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : DRCPGM\100001
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C29215/A20772
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests T.D.H. has a part-time position as Chief Scientific Officer of FoRx Therapeutics, AG.
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