Mechanism and regulation of meiotic recombination

减数分裂中的同源重组对于有性繁殖过程中基因组的完整性是必不可少的，但也是一种 基因组进化的强大决定因素，并使细胞面临突变和染色体重排的风险。 减数分裂重组始于Spo11引起的DNA双链断裂(DSB)。单元格确保DSB 在正确的时间、地点和数量进行制造，以最大限度地提高维修效率并将有害风险降至最低 结果。本研究计划旨在了解减数分裂DSB形成的分子机制和 调节双链断裂和重组的过程。老鼠和酵母菌将被用来 探索染色体生物学的这些关键方面。具体的调查领域包括： ·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。第二条途径抑制DSB 在同源染色体彼此成功接合的地方形成。一个重要的 挑战在于理解这些途径背后的机制。 ·DSB位置是非随机的，这种DSB“景观”对遗传性和 基因组的稳定性。影响DSB格局的因素仍然知之甚少，但最近的进展告诉我们 关于染色体内在因素和反式作用因子作用的机械论假说。这些假设- SES将使用强大的方法进行测试，以在核苷酸分辨率下绘制全基因组的DSB分布图。 ·通过重组修复DSB的一个基本步骤是DNA末端的核外溶解处理，但是 人们对这种机制知之甚少。将开发一种创新的用于DSB切除的全基因组分析 为了定义切除是如何进行的，它是如何被监管的，以及它是如何克服核酸酶的障碍的 通过染色质。 ·重复DNA序列之间的错误、非等位基因重组会导致染色体重排- 可以传给后代的东西。最近的工作在小鼠中发现了容易患上 这样的错误和开发的工具来表征和量化重排。现在面临的重要挑战是 了解这种突变重组的机制，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- 嵌合体只共享一个很小的同源区域(伪常染色体区域，或PAR)，在这个区域内重组- 国家必须出现。PAR重组缺陷会导致不育或性染色体错误分离。近期 研究表明，PAR在减数分裂过程中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被发现了。将解决有关以下方面的关键问题 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.