Grant: Project Grant

The 2015 Nobel Prize in Chemistry was shared between Paul Modrich, Tomas Lindahl, and Aziz Sancar, who pioneered research into mechanisms of DNA repair. DNA repair is essential for the recognition and subsequent repair of damaged or aberrant DNA molecules. This is a critical process for cellular health as it prevents genome instability, which is the accumulation of mutations or DNA rearrangements within the genome. The importance of understanding molecular mechanisms of how DNA repair maintains genome stability is important for human health, as genome instability is a hallmark of both cancer and neurodegenerative diseases. Indeed, inherited mutations in DNA repair genes can lead to severe human diseases, such as Fanconi anemia and Ataxia telangiectasia, or can result in cancer predisposition. However, once cancer has formed the DNA repair defects that are often specific to the cancer cell can be a good thing. Recent clinical approaches have shown that a class of drugs called PARP inhibitors, which specifically kill cancer cells by targeting their DNA repair defect, can be used to treat advanced ovarian cancer. These PARP inhibitors target defects in the DNA repair pathway called homologous recombination repair. Homologous recombination repair is involved in the repair of DNA double-strand breaks that are one of the most toxic forms of DNA damage as both strands of the DNA double-helix are broken, which can lead to their separation and loss of genetic information or large rearrangements of DNA within the genome. The goals of this project are to understand the molecular mechanisms of how homologous recombination repair works to accurately fix these double-stranded DNA breaks. This will help us understand how this essential process works, how it protects against cancer, how cancer or other disease states arise when this pathway is defective, and how we can target this pathway for future advanced cancer therapies.