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: 7538325
• 负责人: Ekaterina Revenkova
• 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/7538325
• 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; Reproductive Biology; Role; Sister Chromatid; Structure; Synaptonemal Complex; Testing; Upper arm; Work; age related; base; cohesin; cohesion; man; protein protein interaction; segregation; telomere

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，这是减数分裂的关键过程 配子发生。在配子发生过程中维持基因组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极高。减数分裂染色质动力学是 它与有丝分裂特别不同，而且还远未被理解。在此续订申请中，我们要求 持续支持我们对减数分裂特异性粘连蛋白 SMCi[3] 的研究，我们已经分离并 在第一个资助期间最初被表征。 SMClp 被证明是减数分裂的核心元件 染色体行为。正如我们所表明的，减数分裂的姐妹染色单体凝聚需要 SMCifJ 染色体，用于减数分裂特异性端粒运动，以及适当的减数分裂 DNA 重组。 现在需要分子、细胞和有机体研究来破译其机制 SMCip 的作用是将其功能置于减数分裂染色体结构和行为的更大背景下，并且 进一步阐明其生物学作用。 我们的中心假设表明 SMCi(3 在决定减数分裂中发挥着特定且重要的作用 染色体结构和动力学，从而避免非整倍体。 特别是，我们提出 SMClp 在特定复合体中有助于联会复合体 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。我们进一步表明 SMCi(3 粘连蛋白复合物的周转是维持 女性减数分裂过程中姐妹染色单体的凝聚力，特别是 dictyate 停滞，因此重要的是要避免 非整倍体。我们的目的是确定 SMClp 在 dictate 逮捕期间和与年龄相关的过程中的作用 非整倍体增加。此外，我们建议 SMCi|3 履行与无处不在的不同功能 SMCicx。我们的目的是检验这些假设。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，我们的结果不仅对于更好地了解哺乳动物SMC很重要 蛋白质生物学，还可以了解染色体结构的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体具有特别重要的意义。恰当的 染色体结构和分离对于减数分裂（即配子发生）至关重要。身份识别和 这些过程所需的蛋白质（例如粘连蛋白）的表征至关重要，而不是 仅适用于基础生物学，但更适用于人类健康，因为人类患有极高的 配子发生过程中出现并导致的染色体异常率，例如，唐氏综合症 综合症。