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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    • "Targeting of Dnmt1 to replication foci occurs in most proliferating cells (Kishikawa et al. 2003, Bostick et al. 2007), however, Dnmt1o/s is largely excluded from the nucleus during early preimplantation stages (Howell et al. 2001), likely to allow for the large-scale demethylation that occurs to both haploid genomes (Figs 1 and 2). Both sperm and oocytes contain parent-of-origin specific 5mC patterns. "
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