The small nematode Caenorhabditis elegans has been used with great success as a model organism for the genetic analysis of programmed cell death. Our long term goal is to use the C. elegans germ line as a genetic model system to understand how apoptosis is regulated in response to various regulatory signals. We show in this application that germ cells respond to two distinct signals: 1. a physiological pathway that is used to limit germ cell numbers, and 2. a checkpoint pathway that activates the apoptotic program in response to DNA damage. To better understand the molecular basis of these two pathways, and how they regulate the common apoptotic effector machinery, we will: 1. Isolate and genetically characterize germ 1ine apoptosis (gla) mutants. 2. Clone and characterize three strong gla genes involved in physiological germ cell apoptosis. 3. Generate and characterize null alleles in five candidate DNA damage checkpoint genes. 4. Isolate and genetically characterize ard mutants that show an abnormal response to DNA damage. 5. Clone two strong ard genes by positional cloning and/or candidate gene approach. We expect that the work described in this application will shed considerable new light on how multiple pro death or pro survival signals can be integrated within a single cell. We also expect to obtain a much better understanding of the genetic pathway(s) that mediate DNA damage response in metazoans. Because mutations in this pathway are likely to alter the sensitivity of tumor cells to DNA damaging agents, we believe that our work has the potential to greatly impact our understanding of how and why tumors can develop resistance to radio and chemotherapy.
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