Meiosis-Specific Cohesin Component, Stag3 Is Essential for Maintaining Centromere Chromatid Cohesion, and Required for DNA Repair and Synapsis between Homologous Chromosomes

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.

Nuclear localization of PRDM9 and its role in meiotic chromatin modifications and homologous synapsis

“…In the mouse, although meiotic recombination initiates prior to and independently of synapsis (Mahadevaiah, et al 2001), synapsis is required for recombination sites to repair DSBs via development into meiotic crossovers (de Vries, et al 2005). Although arrest of Prdm9 -mutant spermatocytes is at a more advanced stage than arrest of most single or double mutants for meiosis-specific cohesins (Fukuda, et al 2014; Hopkins, et al 2014; Llano, et al 2014; Llano, et al 2012), Prdm9 -mutant spermatocytes exhibit synapsis defects that are in common with those described for spermatocytes mutant for other proteins playing early roles in the recombination pathway, e.g., SPO11 and DMC1 (Bannister, et al 2007; Baudat, et al 2000; Pittman, et al 1998; Romanienko and Camerini-Otero 2000). These include delayed and/or inefficient repair of DNA DSBs, persistent RAD51 foci and patches of P-H2AFX (this study; Hayashi et al, 2005).…”

“…Notably, not all of these proteins co-localize within the same cohesin complexes, i.e., there are several different meiosis-specific cohesin complexes, with separate functions not yet fully understood (Revenkova and Jessberger 2006). Specific single ( Stag3 ) or double ( Rec8 - Rad21l ) cohesin subunit mutants exhibit very early meiotic prophase arrest, in the leptotene stage (Fukuda, et al 2014; Hopkins, et al 2014; Llano, et al 2014; Llano, et al 2012), providing evidence that these proteins are essential for setting up a chromosomal architecture favoring recombination and homology pairing. Interestingly, the temporal setting for establishing the cohesin-mediated meiotic chromosome AEs encompasses the time period when PRDM9 is first detected in male germ-cell nuclei.…”

A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis

“…For example, the FSH receptor is required for granulosa cell response to FSH; BMP15, a member of the TGF-β superfamily, is critical for multiple aspects of folliculogenesis and oocyte developmental competence (reviewed in ref. 16); STAG3, a cohesin subunit, and SYCE1, a synaptonemal complex protein, are required for chromosomal segregation in meiosis (10,17); and MCM8 and MCM9 are necessary for meiotic homologous recombination (18).…”

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

“…In addition, cohesin complexes are required for accurate recombination and synapsis between homologous chromosomes (Rankin, 2015). Meiosis-specific cohesin components, including SMC1β, two α-kleisins (REC8 and RAD21L) and a stromal antigen protein (STAG3), are important for these additional requirements of cohesins during meiosis (Bannister et al, 2004;Fukuda et al, 2014;Herrán et al, 2011;Hopkins et al, 2014;Llano et al, 2014;Revenkova et al, 2004;Winters et al, 2014;Xu et al, 2005). Mutation of meiosisspecific cohesin components in female mice results in an increased frequency of oocyte aneuploidy and premature ovarian failure The two condensin complexes (I and II) are composed of the SMC2 and SMC4 heterodimers, but their kleisin subunit and pair of HEAT repeat elements are unique (Hirano, 2015).…”