Trim33 masks a non-transcriptional function of E2f4 in replication fork progression.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 08 2023
23 08 2023
Historique:
received:
12
12
2022
accepted:
14
08
2023
medline:
25
8
2023
pubmed:
24
8
2023
entrez:
23
8
2023
Statut:
epublish
Résumé
Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.
Identifiants
pubmed: 37612308
doi: 10.1038/s41467-023-40847-0
pii: 10.1038/s41467-023-40847-0
pmc: PMC10447549
doi:
Substances chimiques
RecQ Helicases
EC 3.6.4.12
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5143Informations de copyright
© 2023. Springer Nature Limited.
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