Saturday, May 18, 2024
5/18/2024
DESCRIPTION (provided by applicant): Mer1p is produced during meiosis in the yeast Saccharomyces cerevisiae and activates the splicing of at least three introns in genes whose products are required for completion of meiosis. The mRNAs of these genes contain a positive regulatory element, or splicing enhancer, in their introns that binds to Mer1p in vitro. A hypothesis for how Mer1p regulates the splicing of these genes is that Mer1p stabilizes early splicing complexes that form on these introns allowing them to continue assembling into an active spliceosome. Without Mer1p these early splicing complexes lack sufficient stability to continue assembling into an active enzyme. The specific aims of this project include measuring the stability and rates of formation of these complexes with and without Mer1p, and with and without other splicing factors that are critical for Mer1p- activated splicing. This will be achieved with kinetic studies and competition stability studies using splicing extracts and RNAs containing the Mer1p enhancer element. The long-term goals of the PI's research are to understand the mechanisms that govern differential splicing and how aberrant splicing leads to disease in humans. Mer1p contains an evolutionarily conserved KH domain RNA binding motif, and several putative Mer1p homologues can be identified in the human genome. KH domain proteins have been implicated in several diseases in humans including Fragile X Syndrome and Paraneoplastic Disease. Unfortunately there is little understanding of how KH domain proteins regulate splicing. A pursuit of the function of KH domain proteins in a tractable model organism like yeast will facilitate the understanding of the mechanisms of this family of proteins in humans and provide opportunities for the PI to transition into animal model systems. Many diseases and cancers result from the improper metabolism of RNA, which are molecules made from DNA and are used in the production of proteins in cells. Unfortunately there is little understanding of how RNA metabolism is regulated by molecules like the Mer1p protein. This project will elucidate how Mer1p and similar proteins function and will offer important insights towards the basis of diseases like Fragile X Syndrome in humans.
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