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

项目概要： 在减数分裂I前期发生的同源重组是人类生殖所必需的 和其他真核生物。人类减数分裂同源重组的缺陷会导致不育，流产， 和唐氏综合征人MLH 1-MLH 3复合物（MutLγ）参与减数分裂 同源重组，但其在这一过程中的功能尚未确定。除了有钥匙 在减数分裂同源重组中的功能人类MutLγ还具有其他的功能，这些功能还知之甚少。 这些功能之一是三联体重复DNA扩增所必需的，这一过程导致多个 神经退行性疾病MutLγ在减数分裂重组中作用的信息缺乏， 三联体重复DNA扩增是我们对这些关键生物过程理解的一个主要空白。我们 初步的数据支持这样的假设，即人MutLγ作为ATP依赖性内切酶在 减数分裂重组和三重重复DNA扩增。本项目的目的是研究MutLγ及其在细胞内的表达， 并建立了MutLγ和MutLγ依赖的功能测定方法， 机制等在目的1中，我们将研究MutLγ的内切酶和ATP酶活性， MutLγ在减数分裂同源重组和三联体重复不稳定性中的功能的新见解。在 目的2：鉴定与人MutLγ相互作用的蛋白质。拟议研究的结果将 进一步加深我们对MutLγ的理解，并将允许对MutLγ依赖性的机制进行新的研究。 减数分裂重组和三重重复DNA扩增。

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.