Functions of a novel, testis-specific SMC protein

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Of the four eukaryotic structural maintenance of chromosomes (SMC) proteins, the yeast SMC1 and SMC3 proteins were recently shown to be required for mitotic and meiotic sister chromatid cohesion and DNA recombination. Very little is known on the role of mammalian SMC proteins in meiosis, and no cell- or tissue-specific variant of SMC proteins has been reported. This proposal focuses on the cellular, molecular, and organismal analysis of a novel, meiosis-specific SMC protein identified by us, named SMC1beta. SMC1beta is homologous to somatic SMC1 and considered a meiosis-specific isoform. We propose that SMC1beta plays an essential role in mammalian meiosis. This role should be in meiotic sister chromatid cohesion and DNA recombination, and should require interactions with other meiotic proteins, and meiosis-specific protein-DNA structures. Our aim is to determine the developmental stage-specificity of SMC1beta expression in spermatogenesis, to identify and characterize proteins that specifically interact with SMC1beta and to decipher the interaction of SMC1beta with meiotic chromatin. Indications exist for a novel SMC1beta/SMC3 complex, and for a function of SMC1beta in prophase I and in later stages of meiosis. The in vivo function of SMC1beta will be studied by deleting the gene in mice. We expect a meiosis-specific phenotype in the animals. A prominent feature of SMC1beta is a basic C-terminal 28 amino acids sequence. We predict that this unique C-terminal motif contributes to the protein specific molecular and cellular features, which we will analyze. Our work will also establish the novel concept of cell-type specific SMC protein variants. Since we consider SMC1beta a key protein for mammalian meiosis, our results will be important not only for better understanding mammalian SMC protein biology, but also for understanding meiotic chromatin and DNA dynamics, and thus for human reproductive biology and health.