Molecular biology of cohesin in mitotic, postmitotic, and meiotic mammalian cells.

Sister chromatid cohesion is mediated by a multi subunit complex called cohesin whose Smc1, Smc3, and Scc1 subunits form a huge tripartite ring structure. Work in yeast suggests that cohesin associates with chromatin fibres by entrapping them inside its ring. According to this ring model, sister chromatid cohesion arises from co-entrapment of sister fibres inside a single ring. We propose to investigate whether a similar topological principle applies to cohesin in mammalian cells, to address t he mechanisms by which cohesin rings entrap DNAs, builds sister chromatid cohesion during S phase, and dissociates from chromosomes during prophase, to evaluate the longevity of cohesin-mediated cohesion during oogenesis, to compare how oocytes and zygotes respond to a catastrophic loss of cohesion, to establish the mechanisms by which shugoshins protect centromeric cohesion from the prophase pathway during mitosis and from separase during meiosis I, and finally to explore whether cohesin regula tes gene expression during development using similar principles to those by which it holds sister chromatids together. In short, how is DNA entrapped by cohesin rings and how is this entrapment maintained or destroyed during cell division and oogenesis?