Limiting homologous recombination at stalled replication forks is essential for cell viability: DNA2 to the rescue.
Chromosome stability
DNA replication fork
DNA replication stress
DNA2 nuclease–helicase
Homologous recombination
Seckel syndrome
Journal
Current genetics
ISSN: 1432-0983
Titre abrégé: Curr Genet
Pays: United States
ID NLM: 8004904
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
21
08
2020
accepted:
01
09
2020
revised:
27
08
2020
pubmed:
11
9
2020
medline:
1
6
2021
entrez:
10
9
2020
Statut:
ppublish
Résumé
The disease-associated nuclease-helicase DNA2 has been implicated in DNA end-resection during DNA double-strand break repair, Okazaki fragment processing, and the recovery of stalled DNA replication forks (RFs). Its role in Okazaki fragment processing has been proposed to explain why DNA2 is indispensable for cell survival across organisms. Unexpectedly, we found that DNA2 has an essential role in suppressing homologous recombination (HR)-dependent replication restart at stalled RFs. In the absence of DNA2-mediated RF recovery, excessive HR-restart of stalled RFs results in toxic levels of abortive recombination intermediates that lead to DNA damage-checkpoint activation and terminal cell-cycle arrest. While HR proteins protect and restart stalled RFs to promote faithful genome replication, these findings show how HR-dependent replication restart is actively constrained by DNA2 to ensure cell survival. These new insights disambiguate the effects of DNA2 dysfunction on cell survival, and provide a framework to rationalize the association of DNA2 with cancer and the primordial dwarfism disorder Seckel syndrome based on its role in RF recovery.
Identifiants
pubmed: 32909097
doi: 10.1007/s00294-020-01106-7
pii: 10.1007/s00294-020-01106-7
pmc: PMC7599155
doi:
Substances chimiques
Okazaki fragments
0
DNA
9007-49-2
DNA Helicases
EC 3.6.4.-
DNA2 protein, human
EC 3.6.4.12
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1085-1092Références
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