MOLECULAR MECHANISMS OF MEIOTIC RECOMBINATION

减数分裂重组的分子机制

• 批准号: MR/S021248/1
• 负责人: Luca Pellegrini
• 金额: $ 102.86万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021248%2F1
• 关键词: MOLECULAR; MECHANISMS; MEIOTIC; RECOMBINATION

Our germ cells, sperm and egg, form the basis for the generation of new human life. Upon fertilisation, the DNA contained within sperm and egg is combined to provide the full complement of genetic information that defines a unique human being. Germ cells are produced through meiosis, a process of cell division in which genetic information contained in our DNA is reshuffled, to generate diversity in the offspring. Meiosis is a fascinating and complicated process that can frequently go wrong, resulting in either sperm or egg with the incorrect number of chromosomes, or in no germ cell being produced at all, causing miscarriage and infertility. It may also result in children being born with genetic diseases such as Down's syndrome. It is important that we explain the molecular processes of meiosis, so that we can understand how genetic diversity is generated and we can diagnose and possibly intervene when meiosis goes wrong. At the heart of meiosis is the process of genetic exchange between pairs of matching parental chromosomes. During genetic exchange, the chromosomes of each matching pair swap segments of DNA, thus generating novel DNA sequences, in a process known as meiotic recombination. In preparation for the exchange, the chromosomes in each pair must first be brought into alignment with each other. To be paired correctly, the long coils of chromosomal DNA must take up a specific shape, needed to execute the recombination reaction. it is also important that the chromosomes of each matching pair check their alignment, by exchanging homologous DNA strands with their partner at multiple sites along their arms. A large set of proteins are required to carry out the complicated steps of meiotic recombination. Previous research has shown that a large protein structure known as the synaptonemal complex (SC) acts as a molecular scaffold, keeping matching chromosomes together in the correct way for the exchange of DNA to take place. At the same time, dedicated protein enzymes known as recombinases perform the remarkable reactions of homology search and DNA-strand exchange between the aligned chromosomes. The successful outcome of this complex set of reactions leads eventually to the generation of a novel combination of genetic information in each sperm cells, in preparation for fertilisation.Despite the great importance of the reaction of genetic exchange between homologous chromosomes in meiosis, we still know relatively little about the molecular mechanisms that determine the three-dimensional organisation of meiotic chromosomes and their recombination. We plan to discover how Our research will help us improve our molecular understanding of meiotic recombination and explain how defects in its mechanisms, either accidental or inherited, can lead to infertility, miscarriage and genetic disease. In addition, our work will improve our knowledge of the different ways in which human cells organise and handle large chromosomal DNA molecules. This information is important as incorrect sorting of our chromosomes during cellular proliferation, caused by defective packaging of the DNA, can lead to unwanted alterations in the genome and to disease such as cancer.

我们的生殖细胞，精子和卵子，构成了新一代人类生命的基础。受精后，精子和卵子中的DNA结合在一起，提供了完整的遗传信息，定义了一个独特的人。生殖细胞是通过减数分裂产生的，这是一个细胞分裂的过程，在这个过程中，我们DNA中包含的遗传信息被重组，从而在后代中产生多样性。减数分裂是一个迷人而复杂的过程，它经常出错，导致精子或卵子的染色体数量不正确，或者根本不产生生殖细胞，导致流产和不孕。它还可能导致孩子出生时患有唐氏综合症等遗传疾病。解释减数分裂的分子过程是很重要的，这样我们就能理解遗传多样性是如何产生的，当减数分裂出现问题时，我们就能诊断并可能进行干预。减数分裂的核心是配对亲本染色体对之间的遗传交换过程。在基因交换过程中，每一对配对的染色体交换DNA片段，从而产生新的DNA序列，这一过程被称为减数分裂重组。在交换的准备过程中，每对染色体必须首先彼此对齐。为了正确配对，染色体DNA的长圈必须具有特定的形状，这是进行重组反应所必需的。同样重要的是，每对配对的染色体通过在臂上的多个位点与伴侣交换同源DNA链来检查它们的排列。需要大量的蛋白质来完成减数分裂重组的复杂步骤。先前的研究表明，一种被称为突触复合体（SC）的大型蛋白质结构起着分子支架的作用，使匹配的染色体以正确的方式聚集在一起，以便进行DNA交换。同时，被称为重组酶的专用蛋白酶在排列的染色体之间进行显著的同源性搜索和dna链交换反应。这一系列复杂反应的成功结果最终导致每个精子细胞中产生一种新的遗传信息组合，为受精做准备。尽管同源染色体间的遗传交换反应在减数分裂中具有重要意义，但我们对决定减数分裂染色体三维组织及其重组的分子机制仍然知之甚少。我们的研究将帮助我们提高对减数分裂重组的分子理解，并解释其机制中的缺陷，无论是偶然的还是遗传的，如何导致不孕症、流产和遗传性疾病。此外，我们的工作将提高我们对人类细胞组织和处理大染色体DNA分子的不同方式的认识。这些信息很重要，因为在细胞增殖过程中，由于DNA包装缺陷而导致的染色体分类错误，可能导致基因组发生不必要的改变，并导致癌症等疾病。

项目成果

A metal ion-dependent mechanism of RAD51 nucleoprotein filament disassembly

RAD51核蛋白丝分解的金属离子依赖性机制

• DOI: 10.1101/2023.02.18.529066
• 发表时间: 2023
• 作者: Appleby R