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

项目概要： 人类繁殖需要发生在减数分裂 I 前期的同源重组 和其他真核生物。人类减数分裂同源重组缺陷导致不孕、流产、 以及唐氏和特纳综合症。人类 MLH1-MLH3 复合体 (MutLγ) 与减数分裂有关 同源重组，但其在此过程中的功能尚未明确。除了拥有一把钥匙 减数分裂同源重组中的功能 人类 MutLγ 还有其他一些我们知之甚少的功能。 其中一个功能是三联体重复 DNA 扩增所必需的，这一过程会导致多种 神经退行性疾病。缺乏有关 MutLγ 在减数分裂重组中作用的信息 三联体重复 DNA 扩增是我们理解这些关键生物过程的一个主要差距。我们的 初步数据支持这样的假设：人类 MutLγ 在细胞中作为 ATP 依赖性核酸内切酶发挥作用。 减数分裂重组和三联体重复DNA扩增。该项目的目标是研究 MutLγ 及其 潜在的相互作用物并为 MutLγ 和 MutLγ 依赖性的未来研究建立功能测定 机制。在目标 1 中，我们将在检测中研究 MutLγ 的核酸内切酶和 ATP 酶活性，从而产生 对 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 目标 2，我们将鉴定与人类 MutLγ 相互作用的蛋白质。拟议研究的结果将 增进我们对 MutLγ 的理解，并将允许对 MutLγ 依赖性机制进行新的研究 减数分裂重组和三联体重复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.