RPA shields inherited DNA lesions for post-mitotic DNA synthesis.
Cell Cycle
/ genetics
Cell Line
Cell Line, Tumor
DNA
/ genetics
DNA Damage
DNA Repair
DNA Replication
/ genetics
HeLa Cells
Humans
Microscopy, Confocal
Mitosis
/ genetics
Replication Protein A
/ genetics
Telomere
/ genetics
Time-Lapse Imaging
/ methods
Tumor Suppressor p53-Binding Protein 1
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 06 2021
22 06 2021
Historique:
received:
20
05
2020
accepted:
11
05
2021
entrez:
23
6
2021
pubmed:
24
6
2021
medline:
20
7
2021
Statut:
epublish
Résumé
The paradigm that checkpoints halt cell cycle progression for genome repair has been challenged by the recent discovery of heritable DNA lesions escaping checkpoint control. How such inherited lesions affect genome function and integrity is not well understood. Here, we identify a new class of heritable DNA lesions, which is marked by replication protein A (RPA), a protein primarily known for shielding single-stranded DNA in S/G2. We demonstrate that post-mitotic RPA foci occur at low frequency during unperturbed cell cycle progression, originate from the previous cell cycle, and are exacerbated upon replication stress. RPA-marked inherited ssDNA lesions are found at telomeres, particularly of ALT-positive cancer cells. We reveal that RPA protects these replication remnants in G1 to allow for post-mitotic DNA synthesis (post-MiDAS). Given that ALT-positive cancer cells exhibit high levels of replication stress and telomere fragility, targeting post-MiDAS might be a new therapeutic opportunity.
Identifiants
pubmed: 34158486
doi: 10.1038/s41467-021-23806-5
pii: 10.1038/s41467-021-23806-5
pmc: PMC8219667
doi:
Substances chimiques
Replication Protein A
0
Tumor Suppressor p53-Binding Protein 1
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3827Subventions
Organisme : European Research Council
ID : 714326
Pays : International
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