The Functions of Cohesins in Mammalia Meiosis

粘连蛋白在哺乳动物减数分裂中的功能

• 批准号: 116305160
• 负责人: Professor Dr. Rolf Jessberger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/116305160?language=en
• 关键词: Functions; Cohesins; Mammalia; Meiosis

Cohesin is essential for sister chromatid cohesion and critically involved in DNA recombination and repair, regulation of gene expression, telomere protection and possibly other processes. In meiosis, these functions are specifically adapted to serve the unique requirements of genome haploidization. With an additional SMC protein, SMC1β, two additional kleisins, REC8 and RAD21L, and an additional SA-type protein, STAG3, the multitude of cohesin complexes in mammalian meiocytes is much larger than in somatic cells. Yet, we know very little about the features and functions of individual cohesin complexes despite solid indications for specific roles for each of the cohesin proteins and their respective complexes. Our long-term goal is to understand the multiple functions of mammalian meiotic cohesin complexes. In the initial funding period, we focused exclusively on SMC1β complexes. They will remain a major focus, but we will now include specific investigations of other cohesin proteins to start moving towards a more comprehensive understanding. Our aims for the next 3-year-period are: (1) to identify meiotic chromosomal binding sites for SMC3 representing all cohesin complexes, for SMC1β and for other specific cohesin proteins, and to relate these sites to function; (2) to determine the genetic and functional relationship between SMC1β, other meiosis-specific cohesin proteins, and with SMC1α; (3) to clarify the multitude, composition and features of meiocyte cohesin protein complexes. All aims will greatly benefit from our unique assembly of mutant mouse strains, many newly generated within the first funding period, which cover deficiencies in almost all cohesin subunits, carry tagged cohesin protein transgenes, or allow isolation of specific meiocyte populations. Considering our recent demonstration of the role of cohesin in avoiding age-dependent oocyte aneuploidies1,2 according to the cohesin deterioration hypothesis3, we expect the proposed studies to be of central importance not only for understanding mammalian gametogenesis, but also for human health.

黏连蛋白是姐妹染色单体黏连所必需的，并且在DNA重组和修复、基因表达调控、端粒保护和可能的其他过程中起关键作用。在减数分裂中，这些功能特别适合于基因组单倍体化的独特要求。在额外的SMC蛋白SMC 1 β、两种额外的Kleisin REC 8和RAD 21 L以及额外的SA型蛋白STAG 3的情况下，哺乳动物性母细胞中的粘着蛋白复合物的数量比体细胞中的多得多。然而，我们知道很少的特点和功能的单个cohesin复合物，尽管坚实的迹象，具体的作用，为每一个cohesin蛋白质和它们各自的复合物。我们的长期目标是了解哺乳动物减数分裂内聚蛋白复合体的多种功能。在最初的资助期间，我们专注于SMC 1 β复合物。它们将仍然是一个主要的焦点，但我们现在将包括其他cohesin蛋白的具体研究，以开始走向更全面的理解。我们未来3年的目标是：（1）鉴定代表所有cohesin复合物的SMC 3、SMC 1 β和其他特异性cohesin蛋白的减数分裂染色体结合位点，并将这些位点与功能联系起来;（2）确定SMC 1 β、其他减数分裂特异性cohesin蛋白和SMC 1 α之间的遗传和功能关系;（3）阐明性母细胞粘附素蛋白复合物的数量、组成和特征。所有目标将大大受益于我们独特的突变小鼠品系，许多新产生的第一个资助期内，其中涵盖了几乎所有的凝聚素亚基的缺陷，携带标记的凝聚素蛋白转基因，或允许特定的性母细胞群体的隔离。考虑到我们最近证明的作用，粘连蛋白在避免年龄依赖性卵母细胞非整倍性1，2根据粘连蛋白恶化hypothesis 3，我们希望拟议的研究是至关重要的，不仅为了解哺乳动物配子发生，而且对人类健康。