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Functions of cohesin SMC1Beta in mammalian meiotic chromosome structure and dynam

粘连蛋白SMC1Beta在哺乳动物减数分裂染色体结构和动态中的功能

基本信息

批准号：
7990600
负责人：
Ekaterina Revenkova
金额：
$ 10.16万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-17 至 2011-11-30
项目状态：
已结题

项目摘要

Sister chromatid cohesion and DNArecombination are at the heart of meiosis, which is a key process for gametogenesis. Maintenance ofgenome integrity during gametogenesis is of utmost medical importance, considering the extraordinarily high incidence of aneuploidies in man. Meiotic chromatin dynamics is specifically distinct from mitotic, and is far from being understood. In this application for renewal, we ask for continuous support of our studies on a meiosis-specific cohesin protein, SMCi[3, that we have isolated and initially characterized during the first grant period. SMClp turned out to be a central element of meiotic chromosome behavior. As we showed, SMCifJ is required for sister chromatid cohesion of meiotic chromosomes, for meiosis-specific telomere movements, and for proper meiotic DNA recombination. Molecular, cellular and organismal studies are now needed to decipher the mechanisms through which SMCip works, to put its function into the larger context of meiotic chromosome structure and behavior, and to further elucidate its biological role. Our central hypothesis suggests that SMCi(3 plays a specific and essential role in determining meiotic chromosome structure and dynamics and thus in avoiding aneuploidies. In particular, we propose that SMClp, within specific complexes, contributes to synaptonemal complex formation and the organization of axis and chromatin loops. We also predict that SMClp plays a direct role in telomere function. We further suggest that turnover of the SMCi(3 cohesin complexis key to maintenance of sister chromatid cohesion during female meiosis, specifically dictyate arrest, and thus important to avoid aneuploidies. Our aim is to determine the role of SMClp during dictyate arrest and in the age-related increase in aneuploidies. In addition we propose that SMCi|3 fulfills distinct functions from the ubiquitous SMCicx. Our aim is to test these hypotheses. Since the available evidence suggests SMCip to be a key protein in mammalian meiosis, our results will be important not only for a better understanding of mammalianSMC protein biology, but also for understanding of meiosis-specificfeatures of chromosome structure, and thus for human reproductive biology and health with particular significance for prevention of aneuploidy. Proper chromosome structure and segregation are essential for meiosis, i.e.gametogenesis. The identification and characterization of proteins required for these processes, such as cohesins, is of paramount importance not only for basic biology, but even more so for human health, since man suffers from an extraordinarilyhigh rates of chromosomal abnormalities that emerge during gametogenesis and cause, for example, Down syndrome.

姐妹染色单体凝聚和DNA重组是减数分裂的核心，这是一个关键过程，配子发生在配子发生过程中保持基因组的完整性具有极其重要的医学意义，考虑到人类非整倍体的发生率非常高，与有丝分裂有明显区别，而且还远未被理解。在此更新申请中，我们要求持续支持我们对减数分裂特异性粘附蛋白SMCi[3]的研究，我们已经分离并在第一个补助期内初步确定。SMClp被证明是减数分裂的中心元件染色体行为如我们所示，SMCifJ是减数分裂中姐妹染色单体凝聚所必需的。染色体，用于减数分裂特异性端粒运动，以及用于适当的减数分裂DNA重组。现在需要分子、细胞和生物体的研究来破译 SMCip的工作原理是将其功能置于减数分裂染色体结构和行为的更大背景中，以进一步阐明其生物学作用。我们的中心假设表明SMCi（3）在决定减数分裂中起着特殊的和重要的作用染色体结构和动力学，从而避免非整倍性。特别是，我们提出SMClp，在特定的复合物，有助于联会复合物，轴和染色质环的形成和组织。我们还预测SMClp在以下方面发挥直接作用：端粒功能我们进一步认为，SMCi β粘附素复合物的周转是维持细胞增殖的关键。姐妹染色单体凝聚在女性减数分裂，特别是dictyate停滞，因此重要的是要避免非整倍性我们的目的是确定SMClp在齿状回阻滞和年龄相关的非整倍性增加。此外，我们建议SMCi| 3实现了与无处不在的 SMCicx。我们的目标是检验这些假设。由于现有证据表明SMCip是一种关键蛋白质，在哺乳动物减数分裂中，我们的研究结果不仅对更好地理解哺乳动物SMC具有重要意义，蛋白质生物学，而且还用于了解染色体结构的减数分裂特异性特征，对人类生殖生物学和健康具有特别重要的意义，用于预防非整倍体。适当染色体结构和分离对于减数分裂即配子发生是必需的。确定和表征这些过程所需的蛋白质，如粘附素，是至关重要的，这不仅是基础生物学的问题，而且对人类健康更是如此，因为人类患有一种异常高的在配子发生过程中出现的染色体异常率，并导致，例如，综合征