Dynamics of replication origin over-activation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 06 2021
08 06 2021
Historique:
received:
17
11
2020
accepted:
19
05
2021
entrez:
9
6
2021
pubmed:
10
6
2021
medline:
16
6
2021
Statut:
epublish
Résumé
Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.
Identifiants
pubmed: 34103496
doi: 10.1038/s41467-021-23835-0
pii: 10.1038/s41467-021-23835-0
pmc: PMC8187443
doi:
Substances chimiques
CDT1 protein, human
0
Cell Cycle Proteins
0
Cyclopentanes
0
Pyrimidines
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3448Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010411
Pays : United States
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