The overarching goals of the Genome Stability Program are to gain new insights into the molecular pathways that maintain genome integrity, how these processes are altered in cancer cells, and finally how these alterations may be exploited to kill tumor cells.
Each cell in the human body suffers an estimated 70,000 DNA lesions per day that arise spontaneously (depurination, deamination, oxidation, replication fork collapse) or from genotoxic insult (UV photoproducts). DNA damage can result from endogenous agents such as reactive oxygen species arising from mitochondria dysfunction or pro-inflammatory pathways, or exogenous environmental factors such as sunlight, radon, and air pollution. These DNA adducts, if not repaired, can cause mutations which also arise from DNA polymerase errors during replication. Mutations in key genes, tumor suppressor genes or activation of oncogenes are associated with the multi-step process of carcinogenesis. DNA damage along with many other factors influence the faithful passage of genetic material from mother to daughter cells, and genome instability including alterations in epigenetic marks, has emerged as one of the key hallmarks of cancer.
Genome Stability research focuses on several essential molecular processes that are disrupted in cancer cells. The specific aims of this Program are to:
- Define the molecular mechanisms of genome instability leading to cancer
- Identify novel therapeutic opportunities created by mutations in DNA repair genes
- Examine functional interactions in telomere maintenance, cellular senescence, and cell death in the processes of cancer and aging
- Develop strategies to sensitize and mitigate responses to ionizing radiation, genotoxic therapeutics and oxidative stress
- Define the functional interactions between DNA damage responses with innate and adaptive immunity
- Recruit, mentor and guide the next generation of cancer researchers working in genome stability.
Because these subjects are overlapping and intimately linked, program members generally work in more than one of these sub-areas. By collaboration and communication, research areas within the Genome Stability Program work synergistically with other Hillman Cancer Center programs for translation of fundamental discoveries in basic science into development of novel targets, drug discovery, and recognition of biomarkers—and, ultimately, hand-off for clinical application to specific cancer types.