Mechanism and regulation of meiotic recombination

 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，但也是基因组多样性、进化和（当发生错误时）不稳定性的有力决定因素。减数分裂重组由Spo 11蛋白产生的双链断裂（DSB）启动。DSB对于成功的减数分裂很重要，但也是可能发生突变或死亡的危险病变，因此细胞确保DSB仅在正确的时间，地点和数量产生。还控制DSB处理和重组以最大化修复效率并最小化有害结果的风险。生殖生物学和基因组完整性中的一个基本问题是理解DSB形成的分子机制以及 调节DSB和重组。小鼠和芽殖酵母S。酿酒酵母将用于探索染色体生物学的这些关键方面。研究的具体领域包括：* 最近的工作发现了一个复杂的电路网络，控制着DSB的数量、时间和分布。一个重要的回路涉及DNA损伤反应激酶ATM的DSB依赖性激活，其反馈以抑制额外的断裂形成。第二，不同的反馈电路抑制DSB形成的同源染色体已经成功地从事彼此的地方。这个网络的轮廓只被粗略地理解;现在的一个重要挑战是定义详细的机制和不同调节回路之间的相互作用。DSB的非随机分布对遗传力和基因组进化具有重要影响，但对DSB景观的形成因素仍知之甚少。这种基本信息的缺乏将使用最近开发的以核苷酸分辨率绘制全基因组DSB分布的强大方法来解决。DSB末端必须被核酸外切酶加工以允许重组，但对该机制知之甚少。一种新的全基因组检测DSB切除已被设计，这将允许前所未有的探索这一重要的，但研究不足，重组方面。重复序列的分散拷贝之间的突变是生殖系突变的一个潜在来源。现在重要的挑战是了解这种非等位基因同源重组的机制，并了解细胞利用的途径，以尽量减少这种风险。性染色体分离在哺乳动物雄性减数分裂中特别令人担忧，因为X和Y染色体仅共享一小部分同源区域（假常染色体区域，或PAR），在该区域内必须发生重组。PAR重组缺陷导致不育或性染色体错误分离。关键问题将得到解决，有关的PAR和精母细胞，确保性染色体分离的保真度的属性。

 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.