The Functions of Cohesins in Mammalia Meiosis

内聚蛋白对姐妹染色单体的内聚至关重要，并在DNA重组和修复、基因表达调控、端粒保护等过程中发挥重要作用。在减数分裂中，这些功能特别适应于满足基因组单倍体化的独特要求。哺乳动物减数细胞中有一个额外的SMC蛋白SMC1β，两个额外的凝血蛋白REC8和RAD21L，以及一个额外的sa型蛋白STAG3，因此，哺乳动物减数细胞中的黏结蛋白复合物的数量要比体细胞大得多。然而，我们对单个内聚蛋白复合物的特征和功能知之甚少，尽管每个内聚蛋白及其各自的复合物具有特定的作用。我们的长期目标是了解哺乳动物减数分裂黏结蛋白复合物的多种功能。在最初的融资期，我们专注于SMC1β复合物。它们仍将是一个主要的焦点，但我们现在将包括对其他黏结蛋白的具体研究，以开始朝着更全面的理解迈进。我们未来3年的目标是：(1)确定SMC3的减数分裂染色体结合位点，SMC1β和其他特定的黏结蛋白代表所有黏结蛋白复合物，并将这些位点与功能联系起来；(2)确定SMC1β和其他减数分裂特异性黏结蛋白与SMC1α之间的遗传和功能关系；(3)阐明减数细胞内聚蛋白复合物的数量、组成和特征。所有目标都将极大地受益于我们独特的突变小鼠菌株组装，许多是在第一个资助期内新产生的，它们覆盖了几乎所有黏附蛋白亚基的缺陷，携带标记的黏附蛋白转基因，或允许分离特定的减数细胞群体。考虑到我们最近根据黏结蛋白退化假说证明了黏结蛋白在避免年龄依赖性卵母细胞非整倍体1,2中的作用，我们期望所提出的研究不仅对理解哺乳动物配子发生，而且对人类健康具有重要意义。

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.