USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

RecQ Helicases / metabolism DNA Replication / drug effects Humans Werner Syndrome Helicase / metabolism DNA Helicases / metabolism Telomere / metabolism Flap Endonucleases / metabolism Ubiquitin-Specific Proteases / metabolism HeLa Cells HEK293 Cells Telomere Homeostasis / drug effects Chromatin / metabolism

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
16 Sep 2024

Historique:

received: 14 08 2023

accepted: 30 08 2024

medline: 17 9 2024

pubmed: 17 9 2024

entrez: 16 9 2024

Statut: epublish

Résumé

Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

Identifiants

DOI: 10.1038/s41467-024-52250-4 PMID: 39284827

pubmed: 39284827

doi: 10.1038/s41467-024-52250-4

pii: 10.1038/s41467-024-52250-4

doi:

Substances chimiques

RecQ Helicases EC 3.6.4.12

Werner Syndrome Helicase EC 3.6.4.12

DNA Helicases EC 3.6.4.-

DNA2 protein, human EC 3.6.4.12

WRN protein, human EC 3.6.4.12

RECQL4 protein, human EC 3.6.1.-

RECQL5 protein, human 0

Flap Endonucleases EC 3.1.-

Ubiquitin-Specific Proteases EC 3.4.19.12

Chromatin 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

8102

Informations de copyright

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