Mechanism and regulation of meiotic recombination

减数分裂重组的机制和调控

基本信息

批准号：
9920159
负责人：
Scott Keeney
金额：
$ 45.67万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920159
关键词：
Address Area Back Biological Assay Biology Cells Chromosome Segregation Chromosomes Complex DNA Damage Dangerousness Defect Developmental Disabilities Disease Ensure Evolution Excision Exonuclease Feedback Feeds Genetic Recombination Genome Germ Lines Germ-Line Mutation Heritability Human Lesion Maps Meiosis Meiotic Recombination Methods Molecular Mus Mutate Nucleotides Outcome Pathway interactions Process Property Pseudoautosomal Region Regulation Repetitive Sequence Reproductive Biology Reproductive Health Resolution Saccharomyces cerevisiae Saccharomycetales Sex Chromosomes Shapes Source Spermatocytes Spo11 protein Spontaneous abortion Sterility Time Work X Chromosome Y Chromosome ataxia telangiectasia mutated protein chromosome missegregation chromosome number abnormality egg genome integrity genome-wide homologous recombination male novel public health relevance repaired response risk minimization sperm cell whole genome

项目摘要

DESCRIPTION (provided by applicant): Homologous recombination during meiosis is essential for genome integrity in the germ line, but is also a powerful determinant of genome diversity, evolution, and (when mistakes occur) instability. Meiotic recombination is initiated by double-strand breaks (DSBs) made by the Spo11 protein. DSBs are important for successful meiosis, but are also dangerous lesions that can mutate or kill, so cells ensure that DSBs are made only at the right times, places, and amounts. DSB processing and recombination are also controlled to maximize repair efficiency and minimize risks of deleterious outcomes. A fundamental problem in reproductive biology and genome integrity is to understand the molecular mechanisms of DSB formation and of the processes that regulate DSBs and recombination. Mouse and the budding yeast S. cerevisiae will be used to explore these critical aspects of chromosome biology. Specific areas of inquiry include the following: * Recent work uncovered a complex network of circuits that control the number, timing, and distribution of DSBs. One important circuit involves DSB-dependent activation of the DNA damage-response kinase ATM, which feeds back to inhibit additional break formation. A second, distinct feedback circuit suppresses DSB formation in places where homologous chromosomes have successfully engaged one another. The outlines of this network are understood in only broad strokes; an important challenge now is to define detailed mechanisms and interactions between different regulatory circuits. The nonrandom distribution of DSBs has important consequences for heritability and genome evolution, but factors shaping the DSB landscape remain poorly understood. This lack of essential information will be ad- dressed using powerful methods that were recently developed to map DSB distributions genome-wide at nucleotide resolution. DSB ends must be processed by exonucleases to allow recombination, but little is known about the mechanism. A novel whole-genome assay for DSB resection has been devised that will permit unprecedented exploration of this important, but understudied, aspect of recombination. Recombination between dispersed copies of repetitive sequences is a potent source of germ line mutations. Important challenges now are to understand the mechanisms of this non-allelic homologous recombination and to understand the pathways cells exploit to minimize this risk. Sex chromosome segregation is particularly fraught in mammalian male meiosis because the X and Y chromosomes share only a small region of homology (the pseudoautosomal region, or PAR) within which re- combination must occur. Defects in PAR recombination cause sterility or sex chromosome missegregation. Key questions will be addressed concerning the properties of the PAR and of spermatocytes that ensure the fidelity of sex chromosome segregation.

描述（由适用提供）：减数分裂过程中的同源重组对于种系中的基因组完整性至关重要，但也是基因组多样性，进化和（发生错误时）不稳定的有力决定者。减数分裂重组是由SPO11蛋白产生的双链断裂（DSB）引发的。 DSB对于成功的减数分裂很重要，但也是可能突变或杀死的危险病变，因此细胞确保仅在适当的时间，地点和数量中制造DSB。 DSB处理和重组也受到控制，以最大程度地提高维修效率并最大程度地减少有害结果的风险。生殖生物学和基因组完整性的一个基本问题是了解DSB形成的分子机制以及调节DSB和重组。小鼠和发芽的酵母菌酿酒酵母将用于探索染色体生物学的这些关键方面。特定的查询领域包括以下内容： *最近的工作发现了一个复杂的电路网络，该电路网络控制DSB的数量，时机和分布。一个重要的电路涉及DSB依赖性DNA损伤 - 响应激酶ATM的激活，该激酶会反馈以抑制额外的断裂形成。第二个不同的反馈电路在同源染色体成功接合的地方抑制了DSB的形成。该网络的概述仅以广泛的笔触才能理解。现在的一个重要挑战是定义不同调节电路之间的详细机制和相互作用。 DSB的非随机分布对遗传力和基因组进化具有重要的后果，但是塑造DSB景观的因素仍然鲜为人知。缺乏基本信息将使用最近开发的强大方法来绘制核苷酸分布的DSB分布。 DSB的末端必须通过外切除酶处理以允许重组，但对该机制知之甚少。已经设计了一种新型的DSB切除术全基因组测定法，它将允许对重组的这一重要但知识的方面进行前所未有的探索。重复序列的分散副本之间的重组是生殖系突变的潜在来源。现在的重要挑战是了解这种非平行性同源重组的机制，并了解细胞利用途径以最大程度地降低这种风险。性染色体分离尤其是在哺乳动物男性减数分裂中造成的，因为X和Y染色体只有一小部分同源性区域（假阳性体区域或PAR），必须在其中进行重新组合。 par重组的缺陷会导致不育或性别染色体错误地分析。将解决有关确保性别染色体分离的忠诚度的PAR和精子细胞的特性的问题。