The molecular basis for the beneficial and deleterious functions of human MLH1-MLH3 complex

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Project summary: Homologous recombination that takes place in prophase of meiosis I is required for reproduction in humans and other eukaryotes. Defects in meiotic homologous recombination in humans cause infertility, miscarriages, and Down and Turner syndromes. The human MLH1-MLH3 complex (MutLγ) has been implicated in meiotic homologous recombination, but its function in this process has not been defined. In addition to having a key function in meiotic homologous recombination human MutLγ has other functions that are poorly understood. One of these functions is required for triplet repeat DNA expansion, a process that causes several neurodegenerative diseases. A lack of information about the action of MutLγ in meiotic recombination and triplet repeat DNA expansion is a major gap in our understanding of these key biological processes. Our preliminary data support the hypothesis that human MutLγ functions as an ATP-dependent endonuclease in meiotic recombination and triplet repeat DNA expansion. The goal of this project is to investigate MutLγ and its potential interactors and establish functional assays for future studies of MutLγ and MutLγ-dependent mechanisms. In Aim 1, we will study endonuclease and ATPase activities of MutLγ in assays that will produce novel insights into the functions of MutLγ in meiotic homologous recombination and triplet repeat instability. In Aim 2, we will identify proteins that interact with human MutLγ. The results of the proposed research will advance our understanding of MutLγ and will permit new studies into the mechanisms of MutLγ-dependent meiotic recombination and triplet repeat DNA expansion.