The goal of this project is to elucidate mechanisms that protect the genetic integrity of individual cells. DNA damage that leads altered gene numbers in individual cells is very common in tumors, and contributes to their progression. Similar damage is thought to occur in many cells in the body over time. Indeed such damage may be a hallmark of the aging process and a contributor to age related diseases including dementia, cardiovascular disease and diabetes, in addition to cancer. By using Drosophila melanogaster mosaic animals that contain cells with differing genotypes to mimic genome alterations, the effects of such somatic genetic diversity can be studied experimentally. The project examines the hypothesis that imbalances in ribosomal protein genes can trigger a 'cell competition' response that removes them in favor or other, genetically-normal cells. The domains of particular ribosomal proteins that are responsible for this additional function, beyond the well-known role of ribosomal proteins in protein synthesis, will be established using structural and functional analysis of clones genes in vivo. Particular attention will be paid to the location within the cell where ribosomal proteins are important, and to the hypothesis that ribosomal protein imbalances activate tumor suppressors of the Salvador-Hippo-Warts pathway to promote elimination of damaged cells. Genetic screens will be conducted that will identify other components of the process, and seek to identify the molecular mechanisms whereby ribosomal protein imbalance leads to cell elimination.
DNA damage that changes the overall gene complement of individual cells contributes to cancer and is thought to occur in aging, increasing the frequency of age-related diseases. This project investigates the mechanisms cells use to detect such genetic changes, and how individual damaged cells may then be recognized and removed.
