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发生率极高，配子发生过程中基因组完整性的维持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明显不同，而且还远未被理解。在本次续展申请中，我们请求持续支持我们对减数分裂特异性粘连蛋白 SMC1B 的研究，该蛋白是我们在第一个资助期间分离并初步表征的。 SMC1B 被证明是减数分裂染色体行为的核心元件。正如我们所表明的，SMC1B 对于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适当的减数分裂 DNA 重组是必需的。现在需要分子、细胞和有机体研究来破译 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下，并进一步阐明其生物学作用。我们的中心假设表明，SMC1B 在确定减数分裂染色体结构和动力学方面发挥着特定且重要的作用，从而避免非整倍体。特别是，我们提出 SMC1B 在特定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 在端粒功能中发挥直接作用。我们进一步表明，SMC1B 粘连蛋白复合物的更新是雌性减数分裂期间维持姐妹染色单体粘连的关键，特别是双磷酸盐停滞，因此对于避免非整倍体很重要。我们的目的是确定 SMC1B 在 dictate 逮捕过程中以及在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。我们的目的是检验这些假设。由于现有证据表明 SMC1B 是哺乳动物减数分裂中的关键蛋白，因此我们的结果不仅对于更好地了解哺乳动物 SMC 蛋白生物学具有重要意义，而且对于了解染色体结构减数分裂特异性特征，从而对于人类生殖生物学和健康对于预防非整倍性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）至关重要。这些过程所需的蛋白质（例如粘连蛋白）的鉴定和表征不仅对于基础生物学至关重要，而且对于人类健康而言更是如此，因为人类在配子发生过程中出现的染色体异常率极高，并导致唐氏综合症等疾病。