The cohesin REC8 prevents illegitimate inter‐sister synaptonemal complex assembly

Abstract

During meiosis, a specialized chromosome structure is assembled to promote pairing/ synapsis of homologous chromosomes and meiotic recombination, a process yielding chiasmata between homologs to ensure accurate segregation. Meiosis-specific cohesin complexes mediating sister chromatid cohesion play pivotal roles in almost all these events, including synaptonemal complex (SC) formation. In this issue of EMBO Reports, Agostinho and colleagues have examined chromosome axes and SC structures by taking advantage of a hypomorphic Stag3 mutant in which the levels of the cohesin subunit REC8 are partly reduced [6]. Using super-resolution microscopy, the authors illuminate previously unforeseen chromosome axis structures, showing locally separated axes in regions where REC8 is absent, regardless of RAD21L or RAD21 cohesin localization. Furthermore, they assessed the relationship between sister chromatid cohesion and inter-sister SC formation, demonstrating that "axial opening" in the REC8-free region is accompanied by illegitimate SC formation between sister chromatids. This study highlights the physiological importance of REC8 in sister chromatid cohesion and proper SC formation during meiosis, suggesting a new model in which a high density of REC8 deposition along the chromosome prevents illegitimate inter-sister SC formation. W hen chromosomes replicate in Sphase, sister chromatids are held together by a mechanism termed sister chromatid cohesion that enables accurate chromosome segregation in both mitosis and meiosis. In somatic cells, sister chromatid cohesion is mediated by the cohesin multi-protein complex, which is comprised of four core subunits: SMC1a and SMC3, the kleisin family protein RAD21, and either one of the accessory subunits SA1 and SA2. In mammalian germ cells, the cohesin complex contains in addition to RAD21 the meiosis-specific kleisin subunits REC8 and RAD21L [1][2][3] (Fig 1A). Furthermore, SMC1a and SA1/SA2 are largely replaced by other meiosis-specific cohesin subunits, SMC1b and STAG3, respectively [4,5]. Given that STAG3, SMC1b, and SMC3 are commonly shared in these meiotic cohesin complexes, it is assumed that the kleisin subunits REC8, RAD21L, and RAD21 have specific roles in the cohesin complexes during meiosis [1,2].In the meiotic prophase, REC8 is localized along chromosomes before meiotic DNA replication and persists throughout the first meiotic division and, at least at centromeres, until metaphase II. In contrast, RAD21L transiently appears on the chromosomes after DNA replication and culminates at the leptotene/ zygotene stage. While RAD21 is detectable in testicular mitotic cells, it is not detected in nuclei from early leptotene until zygotene, in contrast to the patterns of RAD21L and REC8. Thus, the kleisin subunits endow distinct cohesin complexes with different spatiotemporal localization patterns on chromosomes during meiotic prophase. Accumulating evidence suggests that meiosis-specific cohesin complexes play essential roles not only in sister chromatid cohesion, but also in...

The cohesin complex in mammalian meiosis

“…In Rec8 KOs, however, the entire length of the chromosome axis becomes two separate SYCP3‐labeled structures, despite the fully localized RAD21L‐cohesin along the sister chromatid axes (Ishiguro et al., ; Xu et al., ). Similar to the observation in Rec8 KOs, super‐resolution microscopic analyses showed that the chromosome axis is regionally separated in hypomorphic Stag3 mutants and Smc1 β KOs, in which REC8‐cohesin levels are partly reduced (Agostinho, Manneberg, Schendel, Hernandez‐Hernandez, & Kouznetsova, ; Fukuda et al., ; Ishiguro & Watanabe, ). Notably, illegitimate SCs are assembled between sister chromatids at the REC8 free “axial opening” regions in these mutants (Agostinho et al., ; Ishiguro & Watanabe, ), as has also been shown in Rec8 KOs (Bannister et al., ; Xu et al., ).…”

“…Similar to the observation in Rec8 KOs, super‐resolution microscopic analyses showed that the chromosome axis is regionally separated in hypomorphic Stag3 mutants and Smc1 β KOs, in which REC8‐cohesin levels are partly reduced (Agostinho, Manneberg, Schendel, Hernandez‐Hernandez, & Kouznetsova, ; Fukuda et al., ; Ishiguro & Watanabe, ). Notably, illegitimate SCs are assembled between sister chromatids at the REC8 free “axial opening” regions in these mutants (Agostinho et al., ; Ishiguro & Watanabe, ), as has also been shown in Rec8 KOs (Bannister et al., ; Xu et al., ). Thus, REC8 protects the chromosome axis from local “axial opening” and illegitimate SC assembly between sister chromatids (Figure b).…”

Meiotic prophase roles of Rec8 in crossover recombination and chromosome structure

“…COs) along diplotene chromosomes, as illustrated for grasshopper and mouse (14,51,52). Moreover, a recent study using super-resolution microscopy in mouse meiocytes suggests that Rec8 prevents local separation of sister chromatid axes and illegitimate SC assembly (53,54). Studies of Sordaria prophase chromosomes further show that WT chromosomes exhibit axis splitting and loss of axis integrity specifically at CO sites and that this tendency is exaggerated when Rec8 is absent (14).…”

A streamlined cohesin apparatus is sufficient for mitosis and meiosis in the protist Tetrahymena

“…The DSB repair defect may be due to a failure to form chromosome axes. Cohesin has been identified as a part of meiotic chromosome axes (Klein et al 1999 ; Novak et al 2008 ) and is required for SC assembly (Hopkins et al 2014 ; Fukuda et al 2014 ; Ishiguro and Watanabe 2016 ). Rec8 is also a key component of linear elements in Schizosaccharomyces pombe , which does not have a canonical SC structure (Molnar et al 1995 ; Loidl 2006 ; Ding et al 2016 ).…”