During mitosis and meiosis, sister chromatid cohesion resists the pulling forces of microtubules, enabling the generation of tension at kinetochores upon chromosome biorientation. How tension is read to signal the bioriented state remains unclear. Shugoshins form a pericentromeric platform that integrates multiple functions to ensure proper chromosome biorientation. Here we show that budding yeast shugoshin Sgo1 dissociates from the pericentromere reversibly in response to tension. The antagonistic activities of the kinetochore-associated Bub1 kinase and the Sgo1-bound phosphatase protein phosphatase 2A (PP2A)-Rts1 underlie a tension-dependent circuitry that enables Sgo1 removal upon sister kinetochore biorientation. Sgo1 dissociation from the pericentromere triggers dissociation of condensin and Aurora B from the centromere, thereby stabilizing the bioriented state. Conversely, forcing sister kinetochores to be under tension during meiosis I leads to premature Sgo1 removal and precocious loss of pericentromeric cohesion. Overall, we show that the pivotal role of shugoshin is to build a platform at the pericentromere that attracts activities that respond to the absence of tension between sister kinetochores. Disassembly of this platform in response to intersister kinetochore tension signals the bioriented state. Therefore, tension sensing by shugoshin is a central mechanism by which the bioriented state is read.

SummaryCohesin is a conserved ring-shaped multiprotein complex that participates in chromosome segregation, DNA repair, and transcriptional regulation [1, 2]. Cohesin loading onto chromosomes universally requires the Scc2/4 “loader” complex (also called NippedBL/Mau2), mutations in which cause the developmental disorder Cornelia de Lange syndrome in humans [1–9]. Cohesin is most concentrated in the pericentromere, the region surrounding the centromere [10–15]. Enriched pericentromeric cohesin requires the Ctf19 kinetochore subcomplex in budding yeast [16–18]. Here, we uncover the spatial and temporal determinants for Scc2/4 centromere association. We demonstrate that the critical role of the Ctf19 complex is to enable Scc2/4 association with centromeres, through which cohesin loads and spreads onto the adjacent pericentromere. We show that, unexpectedly, Scc2 association with centromeres depends on cohesin itself. The absence of the Scc1/Mcd1/Rad21 cohesin subunit precludes Scc2 association with centromeres from anaphase until late G1. Expression of SCC1 is both necessary and sufficient for the binding of cohesin to its loader, the association of Scc2 with centromeres, and cohesin loading. We propose that cohesin triggers its own loading by enabling Scc2/4 to connect with chromosomal landmarks, which at centromeres are specified by the Ctf19 complex. Overall, our findings provide a paradigm for the spatial and temporal control of cohesin loading.

Summary Meiosis produces gametes through a specialized, two-step cell division, which is highly error prone in humans. Reductional meiosis I, where maternal and paternal chromosomes (homologs) segregate, is followed by equational meiosis II, where sister chromatids separate. Uniquely during meiosis I, sister kinetochores are monooriented and pericentromeric cohesin is protected. Here, we demonstrate that these key adaptations for reductional chromosome segregation are achieved through separable control of multiple kinases by the meiosis-I-specific budding yeast Spo13 protein. Recruitment of Polo kinase to kinetochores directs monoorientation, while independently, cohesin protection is achieved by containing the effects of cohesin kinases. Therefore, reductional chromosome segregation, the defining feature of meiosis, is established by multifaceted kinase control by a master regulator. The recent identification of Spo13 orthologs, fission yeast Moa1 and mouse MEIKIN, suggests that kinase coordination by a meiosis I regulator may be a general feature in the establishment of reductional chromosome segregation.

Meiosis produces gametes through two successive nuclear Background: divisions, meiosis I and meiosis II. In contrast to mitosis and meiosis II, where sister chromatids are segregated, during meiosis I, homologous chromosomes are segregated. This requires the monopolar attachment of sister kinetochores and the loss of cohesion from chromosome arms, but not centromeres, during meiosis I. The establishment of both sister kinetochore mono-orientation and cohesin protection rely on the budding yeast meiosis I-specific Spo13 protein, the functional homolog of fission yeast Moa1 and mouse MEIKIN.Here we investigate the effects of loss of on cohesion Methods: SPO13 during meiosis I using a live-cell imaging approach.Unlike wild type, cells lacking fail to maintain the Results:SPO13 meiosis-specific cohesin subunit, Rec8, at centromeres and segregate sister chromatids to opposite poles during anaphase I. We show that the cohesin-destabilizing factor, Wpl1, is not primarily responsible for the loss of cohesion during meiosis I. Instead, premature loss of centromeric cohesin during anaphase I in cells relies on separase-dependent spo13Δ cohesin cleavage. Further, cohesin loss in anaphase I cells is spo13Δ blocked by forcibly tethering the regulatory subunit of protein phosphatase 2A, Rts1, to Rec8.Our findings indicate that separase-dependent cleavage of Conclusions: phosphorylated Rec8 causes premature cohesin loss in cells. spo13Δ ( ) First published: 4 https://doi.org/10.12688/wellcomeopenres.15066.1 Argüello-Miranda O, Zagoriy I, Mengoli V, et al.: Casein Kinase 1 Coordinates Cohesin Cleavage, Gametogenesis, and Exit from M Phase in Meiosis II. Dev Cell. 2017; 40(1): 37-52. PubMed Abstract | Publisher Full Text Attner MA, Miller MP, Ee LS, et al.: Polo kinase Cdc5 is a central regulator of meiosis I. Proc Natl Acad Sci U S A. 2013; 110(35): 14278-14283. PubMed Abstract | Publisher Full Text | Free Full Text Rolef Ben-Shahar T, Heeger S, Lehane C, et al.: Eco1-Dependent Cohesin Acetylation During Establishment of Sister Chromatid Cohesion. Science. 2008; 321(5888): 563-566. PubMed Abstract | Publisher Full Text Brar GA, Kiburz BM, Zhang Y, et al.: Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis. Nature. 2006; 441(7092): 532-536. PubMed Abstract | Publisher Full Text Buheitel J, Stemmann O: Prophase pathway-dependent removal of cohesin from human chromosomes requires opening of the Smc3-Scc1 gate. EMBO J. 2013; 32(5): 666-676. PubMed Abstract | Publisher Full Text | Free Full Text Buonomo SB, Clyne RK, Fuchs J, et al.: Disjunction of homologous chromosomes in meiosis I depends on proteolytic cleavage of the meiotic cohesin Rec8 by separin. Cell. 2000; 103(3): 387-398. PubMed Abstract | Publisher Full Text Challa K, Fajish VG, Shinohara M, et al.: Meiosis-specific prophase-like pathway controls cleavage-independent release of cohesin by Wapl phosphorylation. PLoS Genet. 2019; 15(1): e1007851. PubMed Abstract | Publisher Full Text | Free Full Text Challa K, Lee MS, Shinohara M, et al...