| Description |
A cell with an irreparably damaged genome is genetically programmed to undergo cell death, called apoptosis. This is to make sure that such cells are not propagating the damaged DNA to their daughter cells, because it will lead to accumulation of genetic instability and is thus detrimental to the tissue or the organ, and to the organism as a whole. In spite of the highly efficient genetic programming to get succumbed to apoptosis, it has been sometimes found that some cells can escape from the fate of apoptosis and continue to survive and proliferate. Accumulation of such cells forms one of the first steps towards the development of cancer. For my dissertation, I have tried to identify the genetic mechanisms that aid a cell to survive DNA damage beyond repair. Thus, this study will help us understand the genetic routes to predisposition towards carcinogenesis and possibly identify new drug targets for cancer therapeutics. Using a highly tractable genetic model organism, the fruitfly, Drosophila melanogaster, I first modeled irreparable DNA damage in the form of a single telomere loss - a mode of DNA damage that cannot be repaired by the DNA repair machinery. This served us as a system to assay the fate of cells following the DNA damage. In this background, I carried out a genetic screen to identify genes that help survival of cells withstanding telomere loss. Here I identified a singular gene, corp, that inhibits P53-dependent cell death by negatively regulating the tumor suppressor, P53. I characterized Corp as the functional analog of vertebrate Mdm2 in the Drosophila system. I identified another gene through the screen - fs(1)Yb, that reduces cell survival following telomere loss possibly by inducing the DDR pathway following telomere loss. Overall, my findings indicate that there are distinct genetic pathways that negatively or positively regulate cell survival following irreparable DNA damage. A tilt towards or away from them causes abnormal proliferation of cells containing damaged genome, thus predisposing an organism to cancer development. |
