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

人类 MLH1-MLH3 复合物有益和有害功能的分子基础

• 批准号: 9893399
• 负责人: Farid Kadyrov
• 金额: $ 7.38万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893399
• 关键词: ATP phosphohydrolase; ATPase Domain; Aneuploidy; Area; Attention; Biological Assay; Biological Process; C-terminal; Cell division; Cells; Chromosome Segregation; Chromosomes; Complex; DNA; DNA Repeat Expansion; Data; Defect; Down Syndrome; Eukaryota; Future; Genetic Materials; Genetic Nondisjunction; Germ Cells; Goals; Health; Human; Human Activities; Infertility; Lead; Link; MLH1 gene; Mammals; Meiosis; Meiotic Recombination; Mismatch Repair; Molecular; Mus; Neurodegenerative Disorders; Organism; Process; Prophase; Proteins; Reproduction; Research; Role; Saccharomycetales; Source; Spontaneous abortion; Sterility; Structure; Testing; Trinucleotide Repeats; Turner' s Syndrome; Yeasts; daughter cell; design; endonuclease; homologous recombination; insight; mutant; novel

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.

项目总结： 发生在减数分裂I前期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孕、流产、 和唐纳氏综合征。人类MLH1-MLH3复合体(MutLγ)与减数分裂有关 同源重组，但其在这一过程中的作用尚未确定。除了有一把钥匙 人类MutLγ在减数分裂同源重组中的作用还有其他一些鲜为人知的功能。 其中一个功能是三联体重复DNA扩增所必需的，这一过程导致了几个 神经退行性疾病。缺乏关于MutLγ在减数分裂重组中的作用的信息 三重重复DNA的扩增是我们对这些关键生物学过程的理解的一大空白。我们的 初步数据支持这样一种假设，即人MutLγ作为一种依赖于ATP的核酸内切酶在体内发挥作用 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 潜在的相互作用因子，并为未来研究MutLγ和MutLγ依赖建立功能分析方法 机制。在目标1中，我们将研究MutLγ的内切酶和ATPase活性，在将产生 对MutLγ在减数分裂同源重组和三联体重复不稳定性中作用的新见解。在……里面 目的2，我们将鉴定与人MutLγ相互作用的蛋白质。拟议的研究结果将 促进我们对MutLγ的理解，并将允许对MutLγ依赖的机制进行新的研究 减数分裂重组和三联体重复DNA扩增。