The Functions of Cohesins in Mammalia 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. In meiosis, these functions are specifically adapted to serve the unique requirements of genome haploidization. With an additional SMC protein, SMC1β, two additional kleisins, REC8 and RAD21L, and an additional SA-type protein, STAG3, the multitude of cohesin complexes in mammalian meiocytes is much larger than in somatic cells. Yet, we know very little about the features and functions of individual cohesin complexes despite solid indications for specific roles for each of the cohesin proteins and their respective complexes. Our long-term goal is to understand the multiple functions of mammalian meiotic cohesin complexes. In the initial funding period, we focused exclusively on SMC1β complexes. They will remain a major focus, but we will now include specific investigations of other cohesin proteins to start moving towards a more comprehensive understanding. Our aims for the next 3-year-period are: (1) to identify meiotic chromosomal binding sites for SMC3 representing all cohesin complexes, for SMC1β and for other specific cohesin proteins, and to relate these sites to function; (2) to determine the genetic and functional relationship between SMC1β, other meiosis-specific cohesin proteins, and with SMC1α; (3) to clarify the multitude, composition and features of meiocyte cohesin protein complexes. All aims will greatly benefit from our unique assembly of mutant mouse strains, many newly generated within the first funding period, which cover deficiencies in almost all cohesin subunits, carry tagged cohesin protein transgenes, or allow isolation of specific meiocyte populations. Considering our recent demonstration of the role of cohesin in avoiding age-dependent oocyte aneuploidies1,2 according to the cohesin deterioration hypothesis3, we expect the proposed studies to be of central importance not only for understanding mammalian gametogenesis, but also for human health.