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Protein Arginine Methyltransferases: Catalytic Mechanisms and Crosstalk in Epigenetics

Abstract

Over the last decade, protein arginine methyltransferases (PRMTs) have emerged as key regulators in epigenetic processes and have been shown to be crucial targets for drug therapies in various types of cancers. As drug-development is progressing, however, it is vital to understand the biochemical nature of these enzymes and what makes them different from other posttranslational modifiers in the epigenetic landscape. To that end, the studies conducted in this work provide novel insights into how PRMTs specify the products they make, how one of the mammalian PRMTs—PRMT7—exhibits a peculiar preference for sub-physiological temperatures, and the first evidence of positive cooperativity observed in PRMTs and potential crosstalk among them. Specifically, a model has been developed which describes the unique aspects of PRMT active sites in way that highlights the role of sterics and overall volume differences between the different types of PRMTs and allows them to produce different methylarginine derivates. Secondly, biophysical techniques in this work show that human PRMT7 preference for colder, sub-physiological temperatures may be caused due to incredibly minute structural changes that need to be more finely measured in vivo and replicated in vitro. Finally, as the field of epigenetic research expanded and the general knowledge of enzymes in this area has grown, more and more evidence for the regulation of these regulators in the way of enzyme crosstalk has been documented. In the case of PRMTs, however, this work shows for the first time that both PRMT1 and PRMT5 display positive cooperativity when methylating histone H4 N-terminal peptides; furthermore, PRMT5’s ability to methylate histone H4 R3 seems to be greatly affected by a prior methylation of H4 R17—a modification carried out by PRMT7.

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