MECHANISMS OF DNA HOMOLOGY-DIRECTED GENOME REPAIR AND TUMOR SUPPRESSION

Genetic studies, first done in model eukaryotes and more recently in mammals, have revealed thathomology-directed DNA repair (HDR) plays a critical role in the elimination of DNA double-strandbreaks and in the preservation of stressed or injured DNA replication forks. HDR is reliant on the tumorsuppressors BRCA1-BARD1, BRCA2, and PALB2, mutations in which cause breast, ovarian, and othercancers. Progress in understanding how these tumor suppressors help mediate HDR and how theirmutational inactivation impacts upon genome integrity has been hampered by the challenge of purifyingthem for mechanistic studies. Our research team has overcome this challenge, which uniquelypositions us to decipher the mechanisms by which these tumor suppressors support HDR. Inconjunction with a growing research team in the NCI-designated Mays Cancer Center at the Universityof Texas Health Science Center at San Antonio and with external collaborators who are leaders instructural biology and single-molecule biophysics, we will dissect the underlying mechanisms ofdifferent stages of HDR, to specifically furnish insights regarding the roles of the aforementioned tumorsuppressors therein. We will also pursue chemical screens and synthesis with the Cancer Preventionand Research Institute of Texas (CPRIT)-supported Center for Innovative Drug Discovery to developinhibitors of HDR to use as a chemical biology tool and for preclinical studies. We are confident that ourholistic approach to deciphering HDR mechanisms will provide the foundation for developing targetedcancer diagnostics and therapeutics.