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The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism

Bashtrykov, Pavel, Jankevicius, Gytis, Jurkowska, Renata Z. ORCID: https://orcid.org/0000-0002-4507-2222, Ragozin, Sergey and Jeltsch, Albert 2014. The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism. Journal of Biological Chemistry 289 (7) , pp. 4106-4116. 10.1074/jbc.M113.528893

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Abstract

The ubiquitin-like, containing PHD and RING finger domains protein 1 (UHRF1) is essential for maintenance DNA methylationby DNA methyltransferase 1 (DNMT1). UHRF1 has been shown to recruit DNMT1 to replicated DNA by the ability of its SET andRING-associated (SRA) domain to bind to hemimethylated DNA. Here, we demonstrate that UHRF1 also increases the activity ofDNMT1 by almost 5-fold. This stimulation is mediated by a direct interaction of both proteins through the SRA domain of UHRF1and the replication focus targeting sequence domain of DNMT1, and it does not require DNA binding by the SRA domain. Disruptionof the interaction between DNMT1 and UHRF1 by replacement of key residues in the replication focus targeting sequence domainled to a strong reduction of DNMT1 stimulation. Additionally, the interaction with UHRF1 increased the specificity of DNMT1for methylation of hemimethylated CpG sites. These findings show that apart from the targeting of DNMT1 to the replicatedDNA UHRF1 increases the activity and specificity of DNMT1, thus exerting a multifaceted influence on the maintenance of DNAmethylation

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 31 October 2019
Date of Acceptance: 21 October 2013
Last Modified: 03 May 2023 11:59
URI: https://orca.cardiff.ac.uk/id/eprint/126453

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