Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.
Sci Adv
; 10(35): eadp0975, 2024 Aug 30.
Article
en En
| MEDLINE
| ID: mdl-39196936
ABSTRACT
During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Unión Proteica
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Histonas
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Nucleosomas
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Islas de CpG
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Metilación de ADN
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ADN (Citosina-5-)-Metiltransferasas
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Ubiquitinación
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ADN Metiltransferasa 3A
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Neoplasias
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article