The Uhrf1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase Dnmt1 by an allosteric mechanism [DNA and Chromosomes]

December 24th, 2013 by Bashtrykov, P., Jankevicius, G., Jurkowska, R. Z., Ragozin, S., Jeltsch, A.

The Ubiquitin-Like Containing PHD and RING Finger Domains Protein 1 (Uhrf1) is essential for maintenance DNA methylation by the 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 Foci Targeting Sequence (RFTS) 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 RFTS 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 Dnmt1's activity and specificity, thus exerting a multifaceted influence on the maintenance of DNA methylation.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on The Uhrf1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase Dnmt1 by an allosteric mechanism [DNA and Chromosomes]