Thomas E. Wilson, M.D., Ph.D.

Research

Cancer is the end result of genetic mutations that lead to a growth advantage and expansion of rare cellular clones. Genetic mutations, in turn, represent the failure of a cell to correctly repair the DNA lesions that are caused by a variety of damaging agents. Specifically, inefficient repair of DNA double-strand breaks (DSBs) leads to a persistence of lesions that ultimately become substrates for chromosomal rearrangement, a hallmark of malignancy. The long-term goal of our laboratory is to evaluate the hypothesis that different types of DSB repair deficiencies lead to the accumulation of distinct DNA lesions or repair intermediates, and that these have a differential likelihood of contributing to rearrangement. This will require a detailed understanding of the nature of DSB intermediates and repair processes. To achieve our goal, we are systematically examining both enzymatic and structural DSB repair proteins and how these interact to achieve the sequence of biochemical events that results in repair. This is being done using novel assays developed in the genetically tractable model organism Saccharomyces cerevisiae, since it is now clear that the fundamental mechanisms of DSB repair and rearrangement are preserved in all eukaryotes. Areas of particular interest are first to examine the factors that impact the choice between the two major pathways of DSB repair (homologous and nonhomologous). Second, we are continuing to identify and characterize the enzymes that process damaged terminal bases and ligate DSB ends. Third, we are working to establish how these various proteins interact to create the nonhomologous end-joining (NHEJ) “repairosome”. Finally, we are examining how perturbations in the above impact the development of chromosomal aberrations.