Characterization of the Synapis Checkpoint in C. elegans Meiosis

减数分裂从二倍体细胞产生单倍体配子，使得二倍体基因组在减数分裂后恢复。 受精减数分裂期间染色体的正确分离取决于 减数分裂前期，如同源染色体的配对和联会以及交换 重组染色体分离的错误通常对受精卵是致命的，但也可能导致 癌症易感性或严重的发育障碍。我发现了一个减数分裂检查点， 响应同源突触中的缺陷，独立于DMA损伤/重组检查点，和 激活细胞凋亡以避免非整倍体配子的产生。不是所有的非突触序列都有 触发这个检查点的能力;相反，这个通路是由非突触配对特异性激活的。 中心（PC），染色体位点，促进突触在C。优雅此外，检查站 需要C。PCH 2是一种芽殖酵母粗线期检查点基因， 检测突触失效的分子机制是广泛保守的。 我计划进一步描述这个突触检查点。我特别感兴趣的是筹委会在以下方面的贡献： 突触检查点激活。与因子相互作用的蛋白质的鉴定和表征 PC功能所需的基因将提供对该位点在非突触时如何激活检查点的深入了解。 研究解决了非突触染色体上异染色质的调节以及PC如何可能 还将进行抑制DMA损坏检查点。我将确定联会丝的作用 通过表征与SC相互作用的两个基因， 通过初步的RNA干扰（RNAi）实验，检查点需要。我会调查 已知的检查点组分pch-2的功能和调节; GFP-PCH-2融合蛋白将被 定位于各种遗传背景中，并提供试剂来鉴定相互作用的蛋白质 生物化学此外，我将通过进行RNAi来识别检查点的其他组件， 筛选将集中于满足特定表达和表型特征标准的候选基因。 这些互补的方法将使我能够从分子和机制上理解 监测同源物突触以及未突触的或不适当突触的同源物如何产生突触。 检查点信号，其最终转化为凋亡反应。 减数分裂产生配子，如卵子和精子。检查点监测减数分裂事件，以确保 配子有正确的染色体数目。如果一个配子的染色体数目不正确， 受精产生的胚胎通常是不能存活的。偶尔，胚胎会遗传一个额外的 不致命但可导致癌症倾向或严重发育缺陷的染色体。

Meiosis generates haploid gametes from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions depends on events in meiotic prophase, such as the pairing and synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or serious developmental disorders. I have identified a meiotic checkpoint that responds to defects in homolog synapsis, independent of a DMA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. Not all unsynapsed sequences have the capacity to trigger this checkpoint; rather, this pathway is specifically activated by unsynapsed Pairing Centers (PCs), chromosome sites that promote synapsis in C. elegans. Furthermore, the checkpoint requires the C. elegans homolog of PCH2, a budding yeast pachytene checkpoint gene, suggesting that the molecular mechanism that detects synaptic failure is widely conserved. I plan to further characterize this synapsis checkpoint. I am particularly interested in the PC's contribution to synapsis checkpoint activation. The identification and characterization of proteins that interact with factors required for PC function will provide insight into how this locus activates the checkpoint when unsynapsed. Studies that address the regulation of heterochromatin on unsynapsed chromosomes and how the PC may inhibit the DMA damage checkpoint will also be undertaken. I will determine the role of the synaptonemal complex (SC) in the synapsis checkpoint by characterizing two genes that interact with the SC and appear to be required for the checkpoint by preliminary RNA inteferference (RNAi) experiments. I will investigate the function and regulation of the known checkpoint component, pch-2; a GFP-PCH-2 fusion protein will be localized in a variety of genetic backgrounds as well as provide a reagent to identify interacting proteins biochemically. Furthermore, I will identify additional components of the checkpoint by undertaking an RNAi screen that will focus on candidate genes that fulfill specific expression and phenotypic profile criteria. These complementary approaches will enable me to gain a molecular and mechanistic understanding of how homolog synapsis is monitored and how an unsynapsed or inappropriately synapsed homolog generates a checkpoint signal that is ultimately translated into an apoptotic response. Meiosis produces gametes, such as eggs and sperm. Checkpoints monitor meiotic events to ensure that gametes have the correct number of chromosomes. If a gamete has an incorrect number of chromosomes, the embryo that results from fertilization is often inviable. Occasionally, an embryo inherits an extra chromosome that is not lethal but can cause cancer predisposition or serious developmental defects.