The Roles of Cohesin Regulator Proteins in Mammalian Meiosis

粘连蛋白调节蛋白在哺乳动物减数分裂中的作用

• 批准号: 247235880
• 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: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/247235880?language=en
• 关键词: Roles; Cohesin; Regulator; Proteins; Mammalian

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. To load cohesin onto chromosomes, to maintain its association with chromosomes, and to establish and dissolve sister chromatid cohesion, several pro- and anti-cohesion factors are required in mitosis (pro: ESCO1, ESCO2, Sororin; mostly anti: HDAC8, WAPL, PDS5A, PDS5B). Roles in mammalian meiosis are almost entirely unknown for all of these cohesin regulating factors. It is unclear, how cohesins are loaded upon entry into meiosis and how cohesion is established, maintained and prepared for release later during meiosis. This lack of knowledge is very unsatisfying, since cohesin is central to meiotic cohesion, meiotic chromosome axes-loop architecture, pairing of homologous chromosomes (synapsis), recombination between homologous chromosomes, protection of telomeres of meiotic chromosomes, and chromosome segregation in both meiotic divisions. If any of these processes fails, gametogenesis is either abrogated or proceeds aberrantly with often severe consequences for the offspring such as aneuploidy. Thus, cohesins association with meiotic chromosomes must be tightly regulated. Our long-term aim is to understand these crucial controls. Based on our preliminary data clearly suggesting functions in meiosis, we propose to begin by studying three of the cohesin regulatory factors, ESCO2, HDAC8, and PDS5B, which became now amenable to genetic and biochemical studies. Mouse strains with inducible deficiencies were generated and are to be analyzed using a variety of methods and approaches. Considering our recent demonstration of the key role of cohesin in avoiding age-dependent oocyte aneuploidy (Lister et al., 2010; Revenkova et al., 2010) according to the cohesin deterioration hypothesis (Jessberger, 2010, 2012), we expect the proposed studies to be of central importance not only for understanding mammalian gametogenesis and meiosis, 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。为了将粘附素加载到染色体上，以维持其与染色体的结合，以及建立和溶解姐妹染色单体的粘附，有丝分裂中需要几种亲和抗粘附因子（亲：ESCO 1，ESCO 2，Sororin;主要是抗：HDAC 8，WAPL，PDS 5A，PDS 5 B）。所有这些粘附素调节因子在哺乳动物减数分裂中的作用几乎完全未知。目前尚不清楚，在进入减数分裂时如何加载凝聚素，以及凝聚力如何建立，维持和准备在减数分裂后期释放。这种知识的缺乏是非常不令人满意的，因为粘着蛋白是中央减数分裂凝聚力，减数分裂染色体轴环结构，配对同源染色体（联会），同源染色体之间的重组，保护减数分裂染色体的端粒，和染色体分离在两个减数分裂。如果这些过程中的任何一个失败，配子发生要么被废除，要么异常进行，通常对后代产生严重的后果，如非整倍性。 因此，与减数分裂染色体结合的粘着蛋白必须受到严格的调控。我们的长期目标是了解这些关键控制。基于我们的初步数据清楚地表明在减数分裂中的功能，我们建议开始通过研究三个粘着蛋白调节因子，ESCO 2，HDAC 8和PDS 5 B，现在成为适合遗传和生物化学研究。产生具有诱导缺陷的小鼠品系，并使用多种方法和途径进行分析。考虑到我们最近证明了粘附素在避免年龄依赖性卵母细胞非整倍性中的关键作用（Lister等人，2010; Revenkova等人，2010）根据内聚素退化假说（Cohesin Decomposition Hypothesis）（Biberger，2010，2012），我们期望所提出的研究不仅对于理解哺乳动物配子发生和减数分裂具有核心重要性，而且对于人类健康也是如此。