title: The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism.
abstract: The ubiquitin-like, containing PHD and RING finger domains protein 1 (UHRF1) is essential for maintenance DNA methylation by DNA methyltransferase 1 (DNMT1). UHRF1 has been shown to recruit DNMT1 to replicated DNA by the ability of its SET and RING-associated (SRA) domain to bind to hemimethylated DNA. Here, we demonstrate that UHRF1 also increases the activity of DNMT1 by almost 5-fold. This stimulation is mediated by a direct interaction of both proteins through the SRA domain of UHRF1 and the replication focus targeting sequence domain of DNMT1, and it does not require DNA binding by the SRA domain. Disruption of the interaction between DNMT1 and UHRF1 by replacement of key residues in the replication focus targeting sequence domain led to a strong reduction of DNMT1 stimulation. Additionally, the interaction with UHRF1 increased the specificity of DNMT1 for methylation of hemimethylated CpG sites. These findings show that apart from the targeting of DNMT1 to the replicated DNA UHRF1 increases the activity and specificity of DNMT1, thus exerting a multifaceted influence on the maintenance of DNA methylation.
authors.affiliation: From the Institute of Biochemistry, Faculty of Chemistry, University Stuttgart, D-70569 Stuttgart, Germany and.
authors.forename: Pavel
authors.initials: P
authors.lastname: Bashtrykov
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.forename: Renata Z
authors.initials: RZ
authors.lastname: Jurkowska
authors.forename: Sergey
authors.initials: S
authors.lastname: Ragozin
authors.forename: Albert
authors.initials: A
authors.lastname: Jeltsch
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D018899:CpG Islands / Q000502:physiology*; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D009687:Nuclear Proteins; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse
keywords: Allosteric Regulation; Chromatin; DNA Methylation; DNA Methyltransferase; Enzyme Mechanisms