Functions of cohesin SMC1Beta in mammalian meiotic chromosome structure and dynam

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Sister chromatid cohesion and DNA recombination are at the heart of meiosis, which is a key process for gametogenesis. Maintenance of genome 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, SMC1B, that we have isolated and initially characterized during the first grant period. SMC1B turned out to be a central element of meiotic chromosome behavior. As we showed, SMC1B 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 SMC1B 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 SMC1B plays a specific and essential role in determining meiotic chromosome structure and dynamics and thus in avoiding aneuploidies. In particular, we propose that SMC1B, within specific complexes, contributes to synaptonemal complex formation and the organization of axis and chromatin loops. We also predict that SMC1B plays a direct role in telomere function. We further suggest that turnover of the SMC1B cohesin complex is 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 SMC1B during dictyate arrest and in the age-related increase in aneuploidies. In addition we propose that SMC1B fulfills distinct functions from the ubiquitous SMC1a. Our aim is to test these hypotheses. Since the available evidence suggests SMC1B to be a key protein in mammalian meiosis, our results will be important not only for a better understanding of mammalian SMC protein biology, but also for understanding of meiosis-specific features 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 extraordinarily high rate of chromosomal abnormalities that emerges during gametogenesis and causes, for example, Down syndrome. [unreadable] [unreadable] [unreadable]