UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation.

Autor:	Tiedemann RL; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Hrit J; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Du Q; Epigenetics Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia., Wiseman AK; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Eden HE; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Dickson BM; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Kong X; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 401 N Broadway, Baltimore, MD, USA., Chomiak AA; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Vaughan RM; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Tibben BM; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Hebert JM; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, NY, NY 10065, USA., David Y; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, NY, NY 10065, USA., Zhou W; Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, 3501 Civic Center Blvd, Philadelphia, PA19104, USA., Baylin SB; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 401 N Broadway, Baltimore, MD, USA., Jones PA; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA., Clark SJ; Epigenetics Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.; St. Vincent's Clinical School, University of New South Wales, 390 Victoria Street, Darlinghurst, NSW 2010, Australia., Rothbart SB; Department of Epigenetics, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Dec 11; Vol. 52 (22), pp. 13733-13756.
DOI:	10.1093/nar/gkae1105
Abstrakt:	The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. The model posits that nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). However, the extent to which DNMT1 relies on ubiquitin signaling through UHRF1 in support of DNA methylation maintenance remains unclear. Here, with integrative epigenomic and biochemical analyses, we reveal that DNA methylation maintenance at low-density cytosine-guanine dinucleotides (CpGs) is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMDs), a methylation signature observed across human cancers. In contrast, UIM2 disruption completely abolishes the DNA methylation maintenance function of DNMT1 in a CpG density-independent manner. In the context of DNA methylation recovery following acute DNMT1 depletion, we further reveal a 'bookmarking' function for UHRF1 ubiquitin ligase activity in support of DNA re-methylation. Collectively, these studies show that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process that is partially reliant on UHRF1 and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to PMD formation in cancers. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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