Probing the complexity of UV induced apoptosis in Drosophila: Apoptosis is an evolutionarily conserved process that has been implicated in a variety of diseases, including cancer and neurodegenerative diseases. Regulation of apoptosis is under the control of a complex network of genes (proteins). Our preliminary data showed that UV induced apoptosis in Drosophila embryo can be mediated by different cell death regulatory genes. More interestingly, the cellular context (differentiation status) of the irradiated cell determines which cell death regulatory gene is activated to induce cell death upon UV irradiation, i.e. When embryos in differentiating stage were irradiated with UV, the reaper gene is induced by a DNA damage -dependent mechanism that involves Drosophila homologue of Ataxia Telangiectasia Mutated, mei-41 (and very likely dP53 as well). However, when embryos prior to differentiating stage were irradiated, the hac-1 (Homologue of Apaf-1 and Ced-4) gene is induced instead of reaper. The induction of hac-1 expression is required for UV induced apoptosis at this developmental stage. But in contrast to UV induction of reaper, UV induction of hac-1 appears to be independent of nuclear DNA damage and was not affected by mei-41 mutation (mei-41 [D5]). It has long been noticed that UV induced cell death can be mediated by DNA damage -dependent and -independent mechanisms. However, it remains unclear as to how are the mechanisms deployed and coordinated to mediate UV induced apoptosis. The aforementioned findings indicate that Drosophila embryo provides an excellent model for systematic analysis of the complexity of UV -induced cell death. The focus of this proposal is to characterize the molecular mechanism underlying UV induced hac- 1 expression and apoptosis in early stage embryos. In addition, we will apply genomic approaches to gain comprehensive understanding of UV -induced genomic response and apoptosis. The goal of this proposal is to elucidate in depth how different cell death regulatory pathways may be deployed to mediate genotoxic stimuli -induced cell death. The information provided by these investigations will contribute to our comprehensive understanding of cell death regulation and skin carcinogenesis. Molecular mechanisms uncovered through this project should provide insights for identifying alternative therapeutic targets, especially for cancers that are resistant to DNA-damage agents.
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