SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1.
Nucleic Acids Res
; 47(17): 9053-9068, 2019 09 26.
Article
em En
| MEDLINE
| ID: mdl-31400111
ABSTRACT
Faithful inheritance of DNA methylation across cell division requires DNMT1 and its accessory factor UHRF1. However, how this axis is regulated to ensure DNA methylation homeostasis remains poorly understood. Here we show that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation. SET8 methylates UHRF1 at lysine 385 and this modification leads to ubiquitination and degradation of UHRF1. In contrast, LSD1 stabilizes both UHRF1 and DNMT1 by demethylation. Importantly, SET8 and LSD1 oppositely regulate global DNA methylation and do so most likely through regulating the level of UHRF1 than DNMT1. Finally, we show that UHRF1 downregulation in G2/M by SET8 has a role in suppressing DNMT1-mediated methylation on post-replicated DNA. Altogether, our study reveals a novel role of SET8 in promoting DNA methylation homeostasis and identifies UHRF1 as the hub for tuning DNA methylation through dynamic protein methylation.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Histona-Lisina N-Metiltransferase
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Metilação de DNA
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Proteínas Estimuladoras de Ligação a CCAAT
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Ubiquitinação
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DNA (Citosina-5-)-Metiltransferase 1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China