DNA double strand break repair mechanisms
Environmental exposure (e.g., radiation, pollution, chemicals, toxins), many physiological processes and therapeutics result in chromosomal single and double strand breaks that must be repaired to maintain genome integrity. Double strand breaks can be repaired rapidly and accurately but are often modified and/or damaged and this can promote erroneous repair outcomes. The resulting diversity in repair products is crucial for many physiological processes but also forms the basis for mutagenesis and chromosomal aberrations that can ultimately lead to tumorigenesis and disease. The underlying molecular strategies that direct correct and error-prone break repair are unknown. A thorough understanding of these strategies is needed to address the wide range of cancers and pathologies induced by the lack of, or malfunctions in, these crucial DNA repair mechanisms. The Jamsen laboratory is focused on uncovering double strand break repair mechanisms. We employ structural biology as a central tool to generate atomic level hypotheses about biological reactions that can be challenged using mechanistic approaches. Using this framework, our overarching goal is to understand how the fundamental mechanisms of repair enzymes function within the molecular architecture of the repair complex to determine repair outcomes in double strand break repair. We employ an integrated approach consisting of cutting-edge structural biology (time-resolved crystallography and Cryo-EM), biochemistry, chemical biology, and molecular biology to reveal fundamental molecular DNA repair strategies and their impact on repair outcomes. This understanding will inform development of mechanism-based therapeutic approaches to modulate DNA repair in cancer and disease.