Recombination pathway and partner choices during meiosis

研究综述 染色体间的相互作用是产生遗传变异、维持基因组完整性的必要条件 通过修复双链DNA断裂（DSB），并确保染色体在 减数分裂，二倍体生物产生单倍体配子的专门细胞分裂程序， 精子和卵子重组中的扰动最终会损害这些基本的细胞功能， 导致癌症不孕不育或出生缺陷减数分裂重组由DSB启动，DSB被修复， 利用有利于利用同源染色体（而不是姐妹染色体）的减数分裂特异性机制 染色单体）作为重组配偶体，并促进DSB修复过程的交叉结果， 这是在减数分裂期间促进适当的染色体分离所必需的。虽然DSB的修复 适当的模板（同源染色体）对于正确的染色体分离是必需的， 基因组的完整性，我们关于生殖细胞如何在存在下实现这种模板偏好的知识， 几乎相同的序列（姐妹染色单体）是有限的。我们研究项目的目标是了解 染色体如何能够访问不同的重组途径和合作伙伴取决于 染色体和细胞环境，以确保忠实的基因组遗传。利用秀丽隐杆线虫作为 模型系统，我们已经开发了一种检测方法，以监测修复诱导DSB与姐妹染色单体 在体内减数分裂前期进行期间。我们现在有证据表明 在减数分裂前期晚期，从同源染色体到姐妹染色单体的配偶体偏好。在 这个建议，我们将开始奠定基础，了解具体的DSB修复途径， 伴侣在减数分裂期间参与和调节。为了确定这些不同的维修伙伴选择 我们将确定与这些基因相关的分子特征、染色体特征和蛋白质。 这些不同的修复结果。此外，我们将使用实时成像，一种新的实时基因组轨迹跟踪系统， 和遗传学来确定早期DSB修复动力学如何影响DSB修复结果。此外，我们将 使用超分辨率和高分辨率显微镜方法来评估DSB修复对减数分裂的影响， 染色体结构和DNA组织。总的来说，这些研究将揭示重组途径如何 和伴侣的选择确保染色体形成染色体分离所必需的连接 并修复DSB以维持精子和卵子发育期间的基因组完整性。

Research Summary Recombination between chromosomes is required to generate genetic variation, maintain genome integrity through the repair of double strand DNA breaks (DSBs), and ensure proper chromosome segregation during meiosis, the specialized cell division program by which diploid organisms generate haploid gametes such as sperm and eggs. Perturbations in recombination can compromise these basic cellular functions, ultimately leading to cancer, infertility, or birth defects. Meiotic recombination is initiated by DSBs, which are repaired using meiosis-specific mechanisms that favor utilization of the homologous chromosome (instead of the sister chromatid) as the recombination partner and that promote a crossover outcome of the DSB repair process, which is required for promoting proper chromosome segregation during meiosis. Although repair of DSBs with the appropriate template (homologous chromosome) is necessary for proper chromosome segregation and genome integrity, our knowledge about how germ cells achieve this template preference in the presence of nearly identical sequences (sister chromatids) is limited. The goal of our research program is to understand how chromosomes are able to access distinct recombination pathways and partners depending on the chromosomal and cellular context to ensure faithful genome inheritance. Using Caenorhabditis elegans as a model system, we have developed an assay to monitor repair of an induced DSB with the sister chromatid during meiotic prophase progression in vivo. We now have evidence for the presence of a switch in repair partner preferences from the homologous chromosome to the sister chromatid during late meiotic prophase. In this proposal we will begin to lay the foundation for understanding how specific DSB repair pathways and partners are engaged and regulated during meiosis. To determine how these different repair partner choices are regulated, we will identify the molecular signatures, chromosomal features, and proteins associated with these different repair outcomes. Further, we will use live imaging, a new live genomic locus tracking system, and genetics to determine the how early DSB repair dynamics influence DSB repair outcomes. Further, we will use superresolution and high-resolution microscopy methods to assess the effects of DSB repair on meiotic chromosome structures and DNA organization. Overall, these studies will reveal how recombination pathway and partner choices ensure that chromosomes form the connections necessary for chromosome segregation and repair DSBs for maintaining genomic integrity during sperm and egg development.