USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment.
Cancer genetics
DNA methylation
Journal
Cell discovery
ISSN: 2056-5968
Titre abrégé: Cell Discov
Pays: England
ID NLM: 101661034
Informations de publication
Date de publication:
2020
2020
Historique:
received:
20
02
2020
accepted:
27
05
2020
entrez:
5
9
2020
pubmed:
5
9
2020
medline:
5
9
2020
Statut:
epublish
Résumé
Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.
Identifiants
pubmed: 32884836
doi: 10.1038/s41421-020-00188-4
pii: 188
pmc: PMC7445300
doi:
Types de publication
Journal Article
Langues
eng
Pagination
58Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 31730048
Organisme : Chinese Ministry of Science and Technology | Department of S and T for Social Development (Department of S&T for Social Development)
ID : 2017YFA054201
Informations de copyright
© The Author(s) 2020.
Déclaration de conflit d'intérêts
Conflict of interestThe authors declare that they have no conflict of interest.
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