Mechanism and regulation of meiotic recombination

减数分裂中的同源重组对于有性生殖过程中的基因组完整性是必不可少的，但也是一个重要的因素。 基因组进化的强大决定因素，并使细胞处于突变和染色体重排的风险中。 减数分裂重组起始于Spo 11产生的DNA双链断裂（DSB）。细胞确保DSB 在正确的时间、地点和数量进行，以最大限度地提高维修效率，并最大限度地减少有害的风险。 结果。本研究旨在了解减数分裂DSB形成的分子机制， DSB和重组的过程。小鼠和酵母菌S.酿酒厂将用于 探索染色体生物学的这些重要方面。具体调查领域包括： ·一个复杂的通路网络控制着DSB的数量、时间和分布。在一条途径中， DNA损伤反应激酶ATM抑制额外断裂的形成。第二种途径抑制DSB 在同源染色体成功地相互接合的地方形成。一个重要 挑战是了解这些途径的机制。 · DSB位置是非随机的，这种DSB“景观”对遗传力有重要影响， 基因组稳定性影响DSB格局的因素仍然知之甚少，但最近的进展表明， 关于染色体内在和反式作用因子作用的机械假说。这些hypothe- 将使用强大的方法在核苷酸分辨率下绘制全基因组DSB分布来测试ses。 ·通过重组修复DSB的一个重要步骤是DNA末端的核酸外切加工，但 关于其机制知之甚少。将开发一种用于DSB切除的创新的新全基因组测定法 定义切除是如何进行的，它是如何调节的，以及它如何克服核酸酶的障碍， 通过染色质。 ·重复DNA序列之间错误的、非等位基因重组会导致染色体重排- 可以传给后代的基因。最近的工作确定了小鼠的基因组位置， 并开发了表征和量化重排的工具。现在的重要挑战是 了解这种诱变重组的机制，并了解细胞如何避免这些错误。 ·在雄性哺乳动物中，性染色体的分离尤其具有挑战性，因为X和Y染色体的分离是非常困难的。 mosomes共享只有一个小区域的同源性（假常染色体区，或PAR），其中重组- 国必须发生。PAR重组缺陷导致不育或性染色体错误分离。最近 工作揭示了PAR在减数分裂期间形成复杂的动态结构。顺式和反式作用 对这种行为至关重要的因素也已被发现。将讨论有关下列方面的关键问题： 确保性染色体重组和分离的机制。

Homologous recombination in meiosis is essential for genome integrity during sexual reproduction, but is also a powerful determinant of genome evolution and puts cells at risk for mutation and chromosome rearrangements. Meiotic recombination initiates with DNA double-strand breaks (DSBs) made by Spo11. Cells ensure that DSBs are made at the right times, places, and numbers to maximize repair efficiency and minimize risks of deleterious outcomes. This research program aims to understand the molecular mechanisms of meiotic DSB formation and of the processes that regulate DSBs and recombination. Mouse and the yeast S. cerevisiae will be used to explore these critical aspects of chromosome biology. Specific areas of inquiry include the following: · A complex network of pathways controls the number, timing, and distribution of DSBs. In one pathway, the DNA damage-response kinase ATM inhibits formation of additional breaks. A second pathway suppresses DSB formation in places where homologous chromosomes have successfully engaged one another. An important challenge is to understand the mechanisms underlying these pathways. · DSB locations are nonrandom, and this DSB “landscape” has important consequences for heritability and genome stability. The factors shaping the DSB landscape remain poorly understood, but recent advances inform mechanistic hypotheses about the roles of both chromosome-intrinsic and trans-acting factors. These hypothe- ses will be tested using powerful methods for mapping DSB distributions genome-wide at nucleotide resolution. · An essential step in the repair of DSBs by recombination is the exonucleolytic processing of DNA ends, but little is known about the mechanism. An innovative new whole-genome assay for DSB resection will be exploited to define how resection is carried out, how it is regulated, and how it overcomes the barrier to nucleases posed by chromatin. · Erroneous, non-allelic recombination between repetitive DNA sequences yields chromosome rearrange- ments that can be passed on to offspring. Recent work identified genomic locations in mice that are prone to such errors and developed tools to characterize and quantify rearrangements. Important challenges now are to understand the mechanisms of this mutagenic recombination and to understand how cells avoid these errors. · In male mammals, segregation of the sex chromosomes is especially challenging because the X and Y chro- mosomes share only a small region of homology (the pseudoautosomal region, or PAR) within which recombi- nation must occur. Defects in PAR recombination cause sterility or sex chromosome missegregation. Recent work has revealed that the PAR develops complex, dynamic structures during meiosis. Cis- and trans-acting factors critical for this behavior have also been uncovered. Key questions will be addressed concerning the mechanisms that ensure sex chromosome recombination and segregation.