Mechanisms of Base Excision DNA Repair

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Abstract: DNA damage arises spontaneously from endogenous and exogenous sources and multiple DNA repair pathways are required to identify and repair sites of damage. Failure to repair damage can result in cell death or mutations. Somatic mutations accumulate as we age and result in a wide spectrum of diseases including cancer. Our long-term goal is to elucidate the molecular mechanisms by which DNA repair enzymes function and identify the key biophysical and biochemical principles that are important for successful DNA repair. A fundamental understanding of DNA repair enzymes is immensely valuable as it provides a framework for understanding the relationships between genotype and phenotype, exposure-induced mutagenesis risks, and in rationally improving treatments that directly or indirectly cause genotoxic stress, such as cancer therapy. This proposal will focus on repair of the most abundant forms of DNA damage both because of the clear biological importance, and because these are excellent model DNA repair systems to elucidate basic principles that may be applied broadly to understanding many DNA repair pathways. We will primarily focus on human enzymes because of the opportunities to immediately translate experimental findings in the context of specific diseases and treatments. We take an interdisciplinary approach to combine different types of structural and biophysical information and to integrate information across multiple time and size scales. This work builds upon our core strength in transient kinetics with rigorous structure/activity analysis. Although the focus of this project is in uncovering the fundamental biological mechanisms for DNA repair, we will combine forces with a diverse set of collaborators who bring unique perspective and training that will allow us to pursue translational and clinical aspects of DNA repair that pertain to specific disease contexts.