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

• 批准号: 7208709
• 负责人: ROLF JESSBERGER
• 金额: $ 32.42万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208709
• 关键词: Aneuploidy; Behavior; Biological; Biology; Centromere; Chromatids; Chromatin; Chromatin Loop; Chromosome Structures; Chromosome abnormality; Chromosomes; Complex; Data; Down Syndrome; Elements; Female; Gametogenesis; Genetic Recombination; Genome; Grant; Health; Heart; Human; Incidence; Maintenance; Medical; Meiosis; Mitotic; Molecular; Movement; Play; Prevention; Process; Proteins; Rate; Reproductive Biology; Role; Sister Chromatid; Structure; Synaptonemal Complex; Testing; Upper arm; Work; age related; base; cohesin; cohesion; man; mouse Smc1l1 protein; mouse Smc1l2 protein; protein protein interaction; segregation; telomere

DESCRIPTION (provided by applicant): Sister chromatid cohesion and DNA recombination are at the heart of meiosis, which is a key process for gametogenesis. Maintenance of genome 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, SMC1B, that we have isolated and initially characterized during the first grant period. SMC1B turned out to be a central element of meiotic chromosome behavior. As we showed, SMC1B 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 SMC1B 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 SMC1B plays a specific and essential role in determining meiotic chromosome structure and dynamics and thus in avoiding aneuploidies. In particular, we propose that SMC1B, within specific complexes, contributes to synaptonemal complex formation and the organization of axis and chromatin loops. We also predict that SMC1B plays a direct role in telomere function. We further suggest that turnover of the SMC1B cohesin complex is 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 SMC1B during dictyate arrest and in the age-related increase in aneuploidies. In addition we propose that SMC1B fulfills distinct functions from the ubiquitous SMC1a. Our aim is to test these hypotheses. Since the available evidence suggests SMC1B to be a key protein in mammalian meiosis, our results will be important not only for a better understanding of mammalian SMC protein biology, but also for understanding of meiosis-specific features 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 extraordinarily high rate of chromosomal abnormalities that emerges during gametogenesis and causes, for example, Down syndrome.

描述（由申请人提供）：姐妹染色单体凝聚和DNA重组是减数分裂的核心，减数分裂是配子发生的关键过程。考虑到人类非整倍体的发生率非常高，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。减数分裂染色质动力学与有丝分裂特别不同，并且还远未被理解。在这份更新申请中，我们要求继续支持我们对减数分裂特异性粘附蛋白SMC1B的研究，我们已经在第一次拨款期间分离并初步鉴定了该蛋白。SMC1B是减数分裂染色体行为的中心元件。正如我们所示，SMC1B是减数分裂染色体的姐妹染色单体凝聚，减数分裂特异性端粒运动，以及正确的减数分裂DNA重组所必需的。现在需要分子、细胞和生物体研究来破译SMC1B的工作机制，将其功能置于减数分裂染色体结构和行为的更大背景中，并进一步阐明其生物学作用。我们的中心假设表明，SMC1B在决定减数分裂染色体结构和动力学，从而避免非整倍性中发挥着特定的和必不可少的作用。特别是，我们提出，SMC1B，在特定的复合物，有助于联会复合体的形成和组织的轴和染色质环。我们还预测SMC1B在端粒功能中起直接作用。我们进一步表明，营业额的SMC1B凝聚素复合物是关键的姐妹染色单体凝聚力的维护在女性减数分裂，特别是dictyate逮捕，从而避免非整倍体。我们的目的是确定SMC1B的作用，在dictyate逮捕和年龄相关的非整倍体的增加。此外，我们建议，SMC1B履行不同的功能，从无处不在的SMC1a。我们的目标是检验这些假设。由于现有的证据表明SMC1B是哺乳动物减数分裂的关键蛋白，我们的研究结果不仅对更好地了解哺乳动物SMC蛋白生物学，而且对了解染色体结构的减数分裂特异性特征，从而对人类生殖生物学和健康具有重要意义，对预防非整倍体具有特殊意义。正确的染色体结构和分离对于减数分裂，即配子发生是必不可少的。这些过程所需的蛋白质（如粘附素）的鉴定和表征不仅对基础生物学至关重要，而且对人类健康更是如此，因为人类在配子发生期间出现的染色体异常率非常高，并导致例如唐氏综合征。