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（由申请人提供）：减数分裂期间的同源重组对于种系中的基因组完整性至关重要，而且也是基因组多样性、进化和（当发生错误时）不稳定性的强大决定因素。由 Spo11 蛋白产生的 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 DSB 仅在右侧产生。 DSB 加工和重组的时间、地点和数量也受到控制，以最大限度地提高修复效率并最大限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 形成及其过程的分子机制。小鼠和芽殖酵母酿酒酵母将用于探索染色体生物学的这些关键方面，具体研究领域包括： * 最近的工作揭示了控制数量、时间和重组的复杂电路网络。 DSB 分布的一个重要回路涉及 DNA 损伤反应激酶 ATM 的 DSB 依赖性激活，它会进行反馈以抑制额外断裂的形成，而第二个独特的反馈回路会抑制同源处的 DSB 形成。染色体已经成功地相互结合，现在我们只能粗略地了解这一网络的轮廓，但现在的一个重要挑战是定义不同调控回路之间的详细机制和相互作用，但 DSB 的非随机分布对遗传性和基因组进化具有重要影响。影响 DSB 景观的因素仍然知之甚少，我们将使用最近开发的强大方法来解决 DSB 分布的问题，这些方法必须通过核酸外切酶来处理全基因组 DSB 分布。重组，但人们对其机制知之甚少。已经设计出一种用于 DSB 切除的新型全基因组测定法，它将允许对重组的这一重要但尚未充分研究的方面进行探索。重复序列的分散副本之间的重组是重组的一个有效来源。现在的重要挑战是了解这种非等位同源重组的机制，并了解细胞利用哪些途径来最大限度地减少这种风险，因为性染色体分离在哺乳动物雄性减数分裂中尤其令人担忧。 X 和 Y 染色体仅共享一小部分同源性区域（假常染色体区域，或 PAR），其中 PAR 重组缺陷会导致不育或性染色体错误分离。确保性染色体分离保真度的精母细胞。