Protein arginine methylation in nuclear organization, function, and stress response

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Post-translational modifications expand the phenotype range of a given genome, thus increasing cellular and organismal adaptability. Protein arginine methyltransferases (PRMT) modify arginine residues to regulate transcription, splicing, translation, and genome integrity; diverse functions conferred by over 4000 arginine methylated proteins in cells. Recent progress enabled the identification of PRMT substrates; however, our knowledge of the effectors, downstream recognition, and function of methyl-arginine remains limited. Most methyl-arginine modified proteins localize in the nucleus, cytoplasm, and some are found in stress granules upon toxic stimuli. PRMT enzymes themselves are found in almost all cellular compartments. While a large body of literature exists on the role of arginine methylation in the cytoplasm and stress granules, little is known about the distribution and dynamics of methyl-arginine in the nucleus, where most arginine methylated proteins reside. We will investigate the nuclear architecture of arginine methylation and its dynamics in stress response using confocal and super-resolution microscopy. Our preliminary data indicates a high abundance of methyl-arginine in discrete nuclear structures that rely on protein-protein and protein-RNA interactions. Arginine residues play critical roles in the protein-protein and protein-RNA interactions; thus, methylation of arginines can dramatically affect the cellular structures built on these interactions. We will modulate the PRMT enzyme activity using selective inhibitors to determine how arginine methylation influences the molecular interaction forces in such model, stress-responsive nuclear structures as paraspeckles. To achieve this, we will employ modern methods to assess protein-protein and protein-RNA interactions in selective compartments as well as identify novel methyl-arginine recognition modules. Our research will provide insights into the molecular mechanism of arginine methylation, the regulation of its dynamics, and its role in the nuclear biology of the stress response. Finally, in our research program, trainees will acquire a diverse set of skills in microscopy, biochemistry, molecular, and cell biology learning in a multidisciplinary environment that will enable them to succeed in their future careers and contribute to Canada's knowledge-based economy.