Functions of cohesin SMC1Beta in mammalian meiotic chromosome structure and dynam

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。在配子发生期间保持基因组的完整性在医学上是极其重要的， 考虑到人类非整倍体的异常高发生率。减数分裂染色质动力学是 特别不同于有丝分裂，而且还远未被理解。在此续期申请书中，我们要求 继续支持我们对减数分裂特异粘附素蛋白Smci[3]的研究，该蛋白是我们分离和 最初的特点是在第一个赠款期间。SMClp被证明是减数分裂的中心成分 染色体行为。如我们所示，SMCifJ是减数分裂姐妹染色单体聚集所必需的 染色体，用于减数分裂特定的端粒运动，以及适当的减数分裂DNA重组。 现在需要分子、细胞和生物体研究来破译 SMCip的工作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，以及 以进一步阐明其生物学作用。 我们的中心假说表明，SMCI(3)在决定减数分裂过程中起着特殊而重要的作用 染色体结构和动态，从而避免非整倍体。 特别是，我们认为SMClp在特定的复合体中参与了联会复合体的形成 轴和染色质环的形成和组织。我们还预测SMClp在 端粒功能。我们进一步认为SMCI(3-粘附素复合体)的周转是维持 姐妹染色单体在雌性减数分裂过程中的聚集，特别是分叉停滞，因此重要的是要避免 非整倍体。我们的目的是确定SMClp在Dictyate逮捕过程中的作用以及在年龄相关的 非整倍体的增加。此外，我们认为SMCI|3实现了与无处不在的 SMCicx。我们的目标是检验这些假说。由于现有证据表明SMCip是一种关键蛋白质 在哺乳动物的减数分裂中，我们的结果不仅对于更好地理解哺乳动物的SMC具有重要意义 蛋白质生物学，但也有助于了解减数分裂特有的染色体结构特征，从而 对人类生殖生物学和健康具有特殊意义的非整倍体的预防。恰如其分 染色体结构和分离是减数分裂即配子发生所必需的。身份识别和 对这些过程所需蛋白质的特性，如粘附素，是至关重要的 仅限于基础生物学，但对人类健康更是如此，因为人类患有异常高的 在配子发生过程中出现的染色体异常率，并导致例如 综合症。

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.