Control of mRNP Dynamics by Protein Arginine Methylation

  Central to eukaryotic gene expression is the proper production of mRNAs. During all steps of their synthesis, mRNAs associate dynamically with a variety of RNA-binding proteins (RBPs), ultimately forming a messenger ribonucleoparticle (mRNP) complex that is exported from the nucleus. Many of the proteins that participate in mRNP formation, including components of the spliceosomal complex, are cotranscriptionally recruited. Given that mRNP biogenesis requires an intricate web of cross-stimulatory molecular connections and physical interdependencies, proper formation of an export-competent mRNP complex requires that such cotranscriptional recruitment takes place in a very precise order.
  Arginine methylation occurs on many of the RBPs involved in mRNP biogenesis. Our previous work established the importance of the major yeast protein arginine methyltransferase, Hmt1 (homolog of human PRMT1), in facilitating proper co-transcriptional recruitment of mRNA-export factors and 3’-end processing factors. We identified an integral component of the U1 snRNP, Snp1, as a substrate of Hmt1. We also showed that Hmt1 promotes proper co-transcriptional recruitment of splicing factors to their genomic targets and, consistent with this observation, regulated splicing is aberrant.
  These findings shed light on how arginine methylation potentially controls an important facet of mRNP formation: pre-mRNA splicing. Given that the disruption of proper pre-mRNA splicing has been linked to a number of important human diseases, delineating the molecular mechanisms by which these events occur is expected to guide us in developing therapeutic strategies that correct or circumvent the disease state.