Abstract
Cohesins are important for chromosome structure and chromosome segregation during mitosis and meiosis. Cohesins are composed of two structural maintenance of chromosomes (SMC1-SMC3) proteins that form a V-shaped heterodimer structure, which is bridged by a α-kleisin protein and a stromal antigen (STAG) protein. Previous studies in mouse have shown that there is one SMC1 protein (SMC1β), two α-kleisins (RAD21L and REC8) and one STAG protein (STAG3) that are meiosis-specific. During meiosis, homologous chromosomes must recombine with one another in the context of a tripartite structure known as the synaptonemal complex (SC). From interaction studies, it has been shown that there are at least four meiosis-specific forms of cohesin, which together with the mitotic cohesin complex, are lateral components of the SC. STAG3 is the only meiosis-specific subunit that is represented within all four meiosis-specific cohesin complexes. In Stag3 mutant germ cells, the protein level of other meiosis-specific cohesin subunits (SMC1β, RAD21L and REC8) is reduced, and their localization to chromosome axes is disrupted. In contrast, the mitotic cohesin complex remains intact and localizes robustly to the meiotic chromosome axes. The instability of meiosis-specific cohesins observed in Stag3 mutants results in aberrant DNA repair processes, and disruption of synapsis between homologous chromosomes. Furthermore, mutation of Stag3 results in perturbation of pericentromeric heterochromatin clustering, and disruption of centromere cohesion between sister chromatids during meiotic prophase. These defects result in early prophase I arrest and apoptosis in both male and female germ cells. The meiotic defects observed in Stag3 mutants are more severe when compared to single mutants for Smc1β, Rec8 and Rad21l, however they are not as severe as the Rec8, Rad21l double mutants. Taken together, our study demonstrates that STAG3 is required for the stability of all meiosis-specific cohesin complexes. Furthermore, our data suggests that STAG3 is required for structural changes of chromosomes that mediate chromosome pairing and synapsis, DNA repair and progression of meiosis.
Highlights
During mitosis, chromosomes are replicated and the resulting sister chromatids are segregated, generating two genetically identical daughter cells
We show that STAG3 is required for normal axial localization and stability of meiosis-specific cohesin subunits SMC1b, REC8 and RAD21L
By analyzing the stromal antigen 3 gene (Stag3) mutant mouse, we have shown that STAG3 is required for stable localization of SMC1b, RAD21L and REC8 to chromosome axes, confirming their interaction in vivo
Summary
Chromosomes are replicated and the resulting sister chromatids are segregated, generating two genetically identical daughter cells. Meiosis I differs from mitosis because homologous chromosomes segregate, whereas sister chromatids remain associated until meiosis II. In order to ensure successful chromosome segregation during meiosis I, three coordinated events occur during prophase I, namely homologous chromosome pairing, synapsis, and recombination [1]. A structural maintenance of chromosomes (SMC) complex known as cohesin is required to hold sister chromatids together prior to the metaphase to anaphase I transition. Meiosis-specific cohesin subunits have been characterized for most model organisms, and are required for the unique events that occur during prophase I.
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