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  • Thumbnail for Screening for ubiquitin ligases involved in Caenorhabditis elegans early embryonic development
    Screening for ubiquitin ligases involved in Caenorhabditis elegans early embryonic development by Lombroso, Adam Paul

    The protein ubiquitination system is a targeted protein degradation pathway that is an essential component of cell cycle progression in mitosis and meiosis. Recent evidence indicates that the ubiquitin system is required for the degradation of zinc finger proteins that play important roles in embryogenesis. It is possible that the ubiquitin system regulates other proteins involved in early embryonic development by controlling which proteins are degraded, and thereby influencing cell fates. In Caenorhabditis elegans (C. elegans), there is a single ubiquitin activating enzyme, which has a well-understood function. The twenty-two ubiquitin conjugating enzymes in C. elegans have been researched to a moderate extent. Finally, there are believed to be about six hundred ubiquitin-protein ligases. Most of these ubiquitin ligases’ exact functions, the proteins they target, remain unknown. Ubiquitin ligases are perhaps the most interesting enzymes in the ubiquitin system because they determine which proteins are targeted for degradation. Two important proteins involved in the embryonic development of C. elegans are posterior alae defective 1 (PAL-1) and muscle excess 3 (MEX-3). PAL-1 is a homeodomain transcription factor protein that is required to specify posterior cell fates. MEX-3 is an RNA-binding protein that binds to pal-1 mRNA in the anterior cells and restricts the translation of PAL-1 to the posterior cells of the embryo, and thereby influences anterior cell fates. Both pal-1 mRNA and MEX-3 protein are present throughout newly fertilized embryos, but by the four-cell stage MEX-3 is depleted in posterior cells and can only bind to pal-1 mRNA in anterior cells, preventing the translation of PAL-1 in these cells. It is thought that MEX-3 depletion in the posterior cells is due to it being targeted by unknown ubiquitin ligases and degraded by the 26S proteasome. Research shows that two homologous mRNA binding proteins (MEX-5 and MEX-6) protect MEX-3 from inactivation and degradation in the anterior, allowing for the repression of PAL-1 translation. One major unanswered question is the identity of the ubiquitin ligase(s) that targets MEX-3 for degradation in the posterior of the embryo. This study attempts to answer that question. RNA interference screening of ubiquitin ligases that are expressed during embryonic development has permitted the identification of 20 ubiquitin ligases that do not target MEX-3 for degradation. Screening of additional ubiquitin ligases may lead to a better understanding of the regulation of many key proteins. By understanding more about the interactions between MEX-3 protein and pal-1 mRNA and how they are regulated, we will learn more about how embryonic development unfolds and what can potentially go wrong.