<scp>STAG</scp>3‐mediated stabilization of <scp>REC</scp>8 cohesin complexes promotes chromosome synapsis during meiosis

Fukuda, Tomoyuki; Fukuda, Natsuki; Agostinho, Ana; Hernández‐Hernández, Abrahan; Kouznetsova, Anna; Höög, Christer

doi:10.1002/embj.201387329

Cited by 95 publications

(130 citation statements)

References 49 publications

(120 reference statements)

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“…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).…”

Section: Discussionmentioning

confidence: 97%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Developmental progress of germ cells through meiotic phases is closely tied to ongoing meiotic recombination. In mammals, recombination preferentially occurs in genomic regions known as hotspots; the protein that activates these hotspots is PRDM9, containing a genetically variable zinc-finger domain and a PR-SET domain with histone H3K4 trimethyltransferase activity. PRDM9 is required for fertility in mice, but little is known about its localization and developmental dynamics. Application of spermatogenic stage-specific markers demonstrates that PRDM9 accumulates in male germ-cell nuclei at pre-leptonema to early leptonema, but is no longer detectable in nuclei by late zygonema. By the pachytene stage, PRDM9-dependent histone H3K4 trimethyl marks on hotspots also disappear. PRDM9 localizes to nuclei concurrently with the deposition of meiotic cohesin complexes, but is not required for incorporation of cohesin complex proteins into chromosomal axial elements, or accumulation of normal numbers of RAD51 foci on meiotic chromatin by late zygonema. Germ cells lacking PRDM9 exhibit inefficient homology recognition and synapsis, with aberrant repair of meiotic DNA double-strand breaks and transcriptional abnormalities characteristic of meiotic silencing of unsynapsed chromatin. Together, these results on the developmental time course for nuclear localization of PRDM9 establish its direct window of function, and demonstrate the independence of chromosome axial element formation from the concurrent PRDM9-mediated activation of recombination hotspots.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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SMC complexes include three major classes: cohesin, condensin and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis have not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre-driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase IIα to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females.

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“…Previously, the same group showed that Stag3 mutant spermatocytes exhibit a hypomorphic phenotype during the progression of meiotic prophase, in which the REC8 cohesin level is partly reduced [5]. This evidence prompted the authors to assess the distribution of REC8 at local "axial opening" regions in the Stag3 mutant.…”

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confidence: 99%

The cohesin REC8 prevents illegitimate inter‐sister synaptonemal complex assembly

Ishiguro

Watanabe

2016

EMBO Reports

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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...

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STAG3‐mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis

Cited by 95 publications

References 49 publications

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

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

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

The cohesin REC8 prevents illegitimate inter‐sister synaptonemal complex assembly

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