The Roles of Cohesin Regulator Proteins in Mammalian Meiosis

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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.