UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science (New York, NY)

Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Science (Impact Factor: 33.61). 10/2007; 317(5845):1760-4. DOI: 10.1126/science.1147939
Source: PubMed


Epigenetic inheritance in mammals relies in part on robust propagation of DNA methylation patterns throughout development. We show that the protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1), also known as NP95 in mouse and ICBP90 in human, is required for maintaining DNA methylation. UHRF1 colocalizes with the maintenance DNA methyltransferase protein DNMT1 throughout S phase. UHRF1 appears to tether DNMT1 to chromatin through its direct interaction with DNMT1. Furthermore UHRF1 contains a methyl DNA binding domain, the SRA (SET and RING associated) domain, that shows strong preferential binding to hemimethylated CG sites, the physiological substrate for DNMT1. These data suggest that UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation.

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Available from: Pierre-Olivier Estève, Jan 13, 2014
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    • "Cell-Cycle-Dependent USP7 Regulation of UHRF1 UHRF1 has emerged as an important epigenetic regulator in the maintenance of DNA methylation through regulating the recruitment and stability of DNMT1 (Bostick et al., 2007; Du et al., 2010; Sharif et al., 2007). This regulation is achieved, in part, through dynamic regulation of UHRF1—both at the level of its chromatin association and ubiquitination—throughout the cell cycle (Gelato et al., 2014; Ma et al., 2012; Taylor et al., 2013). "
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    ABSTRACT: The protein stability and chromatin functions of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) are regulated in a cell-cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of the UHRF1 PBR overlaps with the region engaging in an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-"occluded" state to a state open for multivalent histone binding. Consistently, introduction of a USP7-interaction-defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.046 · 8.36 Impact Factor
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    • "DNMT1, on the other hand, has a preference for hemi-methylated DNA. It is thought to follow the replication fork via interactions with PCNA (Chuang et al. 1997) and UHRF1 (Bostick et al. 2007; Sharif et al. 2007), in restoring DNA CpG methylation on the hemi-methylated DNA after synthesis of the daughter strand. DNA methylation is generally associated with repressed regions of the genome. "
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    ABSTRACT: The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies.
    Chromosoma 07/2015; DOI:10.1007/s00412-015-0530-0 · 4.60 Impact Factor
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    • "Loss of Uhrf1 causes global DNA hypomethylation in human, mouse and zebrafish cells (Bostick et al., 2007; Feng et al., 2010; Hervouet et al., 2010; Sharif et al., 2007; Tittle et al., 2011). In addition, UHRF1 has been implicated in histone deacetylation (Achour et al., 2009; Papait et al., 2008; Unoki et al., 2004) and histone H3 trimethylation [H3K9me3 (Cheng et al., 2013; Kim et al., 2009; Rottach et al., 2010; Fig. 4 "
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