Structural biology of DNA repair The Williams lab applies structural biology approaches to determine molecular mechanisms of genomic instability and cancer. A main interest in the lab is to understand the molecular basis for key steps in the homologous recombination repair (HRR) pathway. HRR plays a critical role in maintaining genomic stability by accurately repairing DNA double strand breaks and inter-strand crosslinks, the most toxic forms of DNA damage, as well as damaged replication forks. The importance of HRR for protecting against cancer is highlighted by inherited mutations in HRR genes (including BRCA1, BRCA2, and the RAD51 paralogs) that predispose to breast and ovarian cancers.
Using hybrid structural techniques, with a focus on combining small-angle X-ray scattering with macromolecular X-ray crystallography, we can determine the structural basis for protein-protein and protein-DNA interactions, as well as the effect of ATP binding and hydrolysis on macromolecular conformational changes and assembly states. Using structure-based insights we design mutations to perturb interactions and activities, which are then used in biochemical and functional assays to inform the underlying biology. Furthermore, our structures and approaches provide a molecular framework that can be used to both understand the effect of disease associated mutations, and to guide the design of future cancer therapies.
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