FUNCTIONS OF A CONSERVED GERMLINE HELICASE IN C.ELEGANS

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DESCRIPTION (provided by applicant): Eukaryotes each appear to encode a single ortholog of CGH- 1 (conserved germline helicase), a DEAD box RNA helicase that is germline-specific in many organisms and required for gametogenesis in yeast. We have shown that C. elegans CGH-1 is specific to the germline and early embryo, and is associated with germline P granules and other putative mRNA-protein particles. cgh-1 is required to form functional gametes, and without it essentially all oocytes die by apoptosis through a germline-specific pathway. This mechanism normally kills up to half of all developing oocytes, apparently so that their cytoplasm is provided to their surviving sisters. Our findings suggest that physiological germline apoptosis, a conserved aspect of gametogenesis, can act as a surveillance mechanism that monitors aspects of germline cytoplasm formation. We hypothesize that CGH- 1 regulates metabolism or translation of particular mRNAs that are stored during gametogenesis, and that elucidation of these functions will yield novel and broadly applicable insights into germline development and apoptosis. We will test these models by elucidating critical aspects of how CGH-l contributes to gametogenesis, and functions at the molecular level. In the latter experiments, we will elucidate the basis for its complex expression pattern, determine whether it interacts functionally with RNA-associated complexes that bind its orthologs in other species, test whether it associates with maternal mRNAs, and use unbiased methods to identify other CGH-1-binding proteins that may be species-specific. These experiments will provide insights into how apoptosis is triggered in developing C. elegans oocytes that may be broadly applicable to understanding why physiological germline cell death occurs. At the same time, they will elucidate post-transcriptional gene regulation mechanisms that may be of conserved importance during gametogenesis, and possibly for proliferation or survival of other stem cell types.