Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The central aim of the parent grant is to identify roles of the proteasome along meiotic chromosomes. The 26S proteasome is the main site of protein degradation in all eukaryotes. It is a compartmentalized, multicomponent protease that resides both in the cytoplasm and the nucleus. Cytoplasmic proteasome functions in eliminating regulatory and misfolded proteins have been recognized for a long time. Functions of the proteasome in the nucleus are much less understood. We recently discovered that during meiosis I, the 26S proteasome is recruited in an evolutionarily conserved manner to chromosomes where it controls homolog pairing, synapsis and recombination. Using a combination of high-resolution microscopy, genetic and proteomic approaches, we are pursuing three aims that build on this discovery: First, we are using tightly controlled conditional alleles to systematically characterize roles during meiosis of different proteasome components. Second, we are identifying substrates of the proteasome relevant to chromosome pairing and recombination, providing insights into a class of molecules that need to be degraded to ensure normal meiotic progression. Third, we are identifying determinants for proteasome recruitment to chromosomes. Meiotic chromosome segregation defects in absence of a functional proteasome emphasize the importance for reproductive health of a better understanding of chromosome- associated proteolysis. Our analysis is also relevant to cancer therapy where proteasome inhibitors have become increasingly important. Many of our approaches involve high resolution and live-cell imaging in the model eukaryote budding yeast. In this supplement proposal, we are requesting funds for an advanced high-resolution, live imaging system as replacement for our aging current microscope. Our current system has given us valuable insights but has become unreliable and is near the end of its lifetime. A state-of-the- art imaging system will enable us to maintain and further enhance a high impact research program into mechanisms of chromosome transmission.
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