My research efforts are focused on understanding highly conserved mismatch repair (MMR) systems, which recognize and repair base pair and small insertion/deletion mismatches that arise as the result of DNA replication errors, DNA damage, and genetic recombination. In humans, mutations in MMR genes correlate with a predisposition to a hereditary form of colorectal cancer (~2 to 7% of all colon cancers) and infertility, underscoring the importance of obtaining new mechanistic understandings of mismatch repair and diagnosis tools. My laboratory has been continuously funded since 1995 by GM53085 and involves long-term collaborations with single molecule biophysicists and population geneticists. The results of our efforts are a novel set of interdisciplinary approaches to study the roles of MMR in maintaining genome stability in yeast during vegetative growth and in meiosis. Our current work is focused on understanding how mismatch recognition proteins identify mismatches and recombination intermediates and signal downstream repair factors. 1. We are identifying novel roles for MLH1-MLH3 in forming interference-dependent crossovers in meiosis. Using genetic and biochemical assays we are studying how the complex acts alone or in concert with other proteins on a variety of DNA substrates, including those predicted to be recombination intermediates (e.g. branched structures, Holliday junctions). 2. We are analyzing the interaction of single MSH and MLH complexes with DNA using total internal fluorescence microscopy. These studies will distinguish between competing models for how MSH and MLH proteins signal downstream steps in MMR. 3. We are using genetic and biochemical approaches to test how MMR components, the SGS1 helicase, and newly identified factors prevent recombination between divergent DNA sequences, with the goal of understanding how such regulation impacts genome stability and cancer susceptibility.
Molecular Biology and Genetics
459 Biotechnology Building
BioG 2990/4990 Credit:
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Undergraduate Students in my lab typically are initially paired with a graduate student to learn basic genetic, biochemical and genomic techniques. They present their work in group meeting and journal club and meet with me on a weekly basis. I ask each student in my lab to work independently as a basic research scientist, with the goal of testing hypotheses that relate to mechanistic questions in DNA repair and meiotic recombination.
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