The Functional Analysis of the Coactivator CARM1

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DESCRIPTION (provided by applicant): Arginine methylation is a widespread posttranslational modification found on both nuclear and cytoplasmic proteins. The methylation of arginine residues is catalyzed by the protein arginine N-methyltransferase (PRMT) family of enzymes, of which there are at least nine members in mammals. PRMTs are evolutionarily conserved and are found from yeast to man, but not in bacteria. The biological consequences of arginine methylation are largely unknown, although with the identification of specific substrates and the recent development of mouse models, functions are emerging. Our goal is to elucidate the biological role of coactivator-associated arginine methyltransferase1 (CARM1), which is transcriptional coactivator. How CARM1 functions as a coactivator is unclear. It methylates histone H3, p300, PABP1 and a subset of splicing factors. We plan to identify and characterize proteins that are recruited to the CARM1 methylated motifs and evaluate the role of CARM1 in splicing. We have generated CARM1 knockout mice, and cells derived from mutant embryos will provide a genetically controlled tool for the in vivo analysis of putative substrates, methyl-dependent binding proteins and splicing studies. Knockin CARM1 mice will also be generated and analyzed to evaluate the importance of this molecules enzymatic activity as opposed to its scaffolding functions. Ultimately, this in-depth analysis of CARM1 function will lead to the mechanistic understanding of a novel class of deregulated enzymes that play a role in a number of disease states and are new targets for drug development.