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(申请人提供)：姐妹染色单体凝聚力和DNA重组是减数分裂的核心，这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是极其重要的医学意义。减数分裂染色质动力学不同于有丝分裂，还远未被理解。在这份续签申请中，我们请求继续支持我们对减数分裂特异粘附素蛋白SMC1B的研究，该蛋白是我们在第一次赠款期间分离并初步鉴定的。SMC1B被证明是减数分裂染色体行为的中心元件。正如我们所显示的，SMC1B是减数分裂染色体姐妹染色单体凝聚、减数分裂特异端粒运动和适当的减数分裂DNA重组所必需的。现在需要分子、细胞和有机学研究来破译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下，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，从而避免非整倍体方面发挥着特殊和重要的作用。特别是，我们认为SMC1B在特定的复合体中，有助于联会复合体的形成以及轴和染色质环的组织。我们还预测SMC1B在端粒功能中起直接作用。我们进一步认为，SMC1B粘附素复合体的周转是在雌性减数分裂过程中维持姐妹染色单体凝聚力的关键，特别是分叉停滞，因此对于避免非整倍体很重要。我们的目的是确定SMC1B在Dictyate阻止和与年龄相关的非整倍体增加中的作用。此外，我们认为SMC1B具有与普遍存在的SMC1a不同的功能。我们的目标是检验这些假说。由于现有证据表明SMC1B是哺乳动物减数分裂中的关键蛋白，我们的结果不仅对于更好地理解哺乳动物SMC蛋白生物学，而且对于了解减数分裂特有的染色体结构特征，从而对于人类生殖生物学和健康，对于防止非整倍体具有特别重要的意义。适当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。鉴定和鉴定这些过程所需的蛋白质，如粘附素，不仅对基础生物学至关重要，对人类健康更是如此，因为人类在配子发生过程中出现的染色体异常率非常高，并导致唐氏综合症等。