{"gene":"SGO1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2006,"finding":"Human SGO1 directly binds to protein phosphatase 2A (PP2A). PP2A localizes to centromeres in a Bub1-dependent manner, and the SGO1-PP2A interaction is required for centromeric localization of SGO1. Depletion of Plk1 by RNAi restores centromeric SGO1 localization in PP2A-depleted cells, indicating that Bub1 targets PP2A to centromeres which counteracts Plk1-mediated removal of SGO1.","method":"Co-immunoprecipitation, RNAi depletion, immunofluorescence localization, epistasis analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi epistasis with multiple orthogonal methods; widely replicated by subsequent studies","pmids":["16580887"],"is_preprint":false},{"year":2012,"finding":"CDK-mediated mitosis-specific phosphorylation of SGO1 activates its cohesion-protection function and enables direct binding of SGO1 to cohesin. The phospho-SGO1-bound cohesin complex contains PP2A, PDS5, and hypophosphorylated sororin, but lacks WAPL. SGO1-PP2A dephosphorylates PDS5-bound sororin, protecting centromeric cohesin from WAPL. Expression of non-phosphorylatable sororin bypasses the requirement for SGO1-PP2A in centromeric cohesion.","method":"In vitro kinase assay, co-immunoprecipitation, RNAi, phospho-mutant expression, rescue experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods including in vitro binding assays and genetic rescue in single rigorous study","pmids":["23242214"],"is_preprint":false},{"year":2015,"finding":"SGO1 is a direct reader of the Bub1-mediated histone H2A-pT120 mark. Bub1 recruits RNA Polymerase II (Pol II) to unattached kinetochores, promoting mitotic transcription. Mitosis-specific inactivation of Pol II traps SGO1 at kinetochores and weakens centromeric cohesion. SGO1 interacts with Pol II in human cells and with RNA in vitro, suggesting Pol II-dependent transcription enables kinetochore-bound SGO1 to reach cohesin embedded in centromeric chromatin.","method":"Co-immunoprecipitation, RNA-binding assay in vitro, Pol II inactivation, immunofluorescence, ChIP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro RNA binding, Pol II inhibition with functional readout) in a single rigorous study","pmids":["26190260"],"is_preprint":false},{"year":2013,"finding":"Cohesin and histone H2A-pT120 specify two distinct pools of SGO1-PP2A: one at inner centromeres (cohesin-bound) and one at kinetochores (H2A-pT120-bound). Bub1 inactivation delocalizes cohesin-SGO1 to chromosome arms. Kinetochore tension triggers SGO1 dephosphorylation and redistributes SGO1 from inner centromeres to kinetochores; incomplete redistribution causes chromosome nondisjunction.","method":"RNAi, phospho-mutant expression, immunofluorescence, tension perturbation experiments","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, phospho-mutants, functional epistasis) establishing two mechanistically distinct SGO1 pools","pmids":["24055156"],"is_preprint":false},{"year":2005,"finding":"Budding yeast Sgo1 is required for sensing lack of tension at the kinetochore in mitosis. SGO1 mutant cells respond normally to microtubule depolymerization but fail to respond to lack of tension, and have difficulty attaching sister chromatids to opposite poles (biorientation defect). Degradation of Sgo1 when sister chromatids separate prevents cell cycle arrest in anaphase.","method":"Genetic mutant analysis, spindle checkpoint assays, chromosome segregation assays in S. cerevisiae","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific mechanistic phenotypic readout; foundational paper replicated extensively","pmids":["15637284"],"is_preprint":false},{"year":2009,"finding":"In Xenopus egg extract reconstitution, Sgo1 plays a role in stabilizing cohesin along chromosome arms during prophase. This stabilizing activity is antagonized by the mitotic kinases Plk1 and Aurora B, which promotes sister chromatid resolution.","method":"Xenopus egg extract in vitro reconstitution, immunodepletion, functional rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in cell-free system with depletion/rescue; single lab but rigorous biochemical approach","pmids":["19696148"],"is_preprint":false},{"year":2008,"finding":"The short splice variant of SGO1 (sSgo1) localizes to the centrosome in interphase and to spindle poles in mitosis. sSgo1 interacts with Plk1, and its spindle pole localization is Plk1-dependent. sSgo1 is required for centriole cohesion; its depletion causes separation of paired centrioles, and this can be suppressed by sSgo1 re-expression or Plk1 knockdown.","method":"GFP localization, co-immunoprecipitation, RNAi, dominant-negative mutant expression, centrosome imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiment and epistasis with Plk1; multiple orthogonal approaches","pmids":["18331714"],"is_preprint":false},{"year":2007,"finding":"NEK2A directly binds human SGO1 in vitro and co-localizes with SGO1 at kinetochores. NEK2A phosphorylates SGO1 at Ser14 and Ser507. Non-phosphorylatable SGO1 mutants perturb chromosome congression and cause increased microtubule attachment errors (syntelic and monotelic attachments), though phosphorylation is not required for SGO1 assembly at kinetochores.","method":"In vitro pulldown, in vitro phosphorylation assay with 32P incorporation, phospho-site mapping, expression of phospho-mutants, immunofluorescence","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with site mapping plus functional phospho-mutant analysis; multiple orthogonal methods in single study","pmids":["17621308"],"is_preprint":false},{"year":2014,"finding":"In budding yeast, Sgo1 together with PP2A-Rts1 ensures localization of condensin to centromeric chromatin. Sgo1 is also required for maintaining Aurora B/Ipl1 localization on kinetochores during metaphase. Thus Sgo1 has a dual function in promoting chromosome biorientation: modulating pericentric chromatin conformation via condensin, and maintaining Aurora B/Ipl1 at kinetochores.","method":"Genetic epistasis, chromatin immunoprecipitation (ChIP), immunofluorescence, yeast genetics","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and ChIP in S. cerevisiae, two orthogonal methods, single lab","pmids":["24945276"],"is_preprint":false},{"year":2008,"finding":"Human SGO1 is degraded during mitotic exit and is a substrate of APC/C-Cdh1. SGO1 contains both a KEN box and a D-box; deletion of either motif alone is insufficient to stabilize SGO1, but simultaneous deletion of both renders it stable. Non-degradable SGO1 does not impair mitotic progression or sister-chromatid separation, indicating SGO1 degradation is not required for these processes. Bub1 contributes to SGO1 steady-state levels via an APC/C-independent mechanism.","method":"Ubiquitination assay in vitro, overexpression/knockdown, deletion mutagenesis, cell cycle synchronization, western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assay plus mutagenesis of degradation motifs with functional cell-based validation; multiple orthogonal methods","pmids":["19015261"],"is_preprint":false},{"year":2005,"finding":"In budding yeast, Sgo1 localizes to cohesin-associated regions (CARs) at the centromere and a 50-kb pericentric domain during meiosis I. Establishment of this domain requires the 120-bp core centromere, Bub1, and the meiosis-specific factor Spo13. Cohesins and kinetochore proteins Iml3/Chl4 are necessary for Sgo1 to associate with pericentric but not core centromeric regions. This 50-kb Sgo1-binding domain is where cohesins are protected from removal during meiosis I.","method":"ChIP, genetic epistasis, localization studies in S. cerevisiae meiosis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-based domain mapping with systematic genetic epistasis; replicated across multiple mutant backgrounds","pmids":["16357219"],"is_preprint":false},{"year":2010,"finding":"SGO1 is first recruited to centromeric heterochromatin in G2 in an HP1-dependent manner that does not require Bub1 kinase activity. In prophase, SGO1 becomes diffusely localized, then returns to centromeres in a Bub1 kinase-dependent manner. Despite the absence of SGO1 from mitotic centromeres when Bub1 kinase is absent, centromeric cohesion is maintained, suggesting the G2 recruitment establishes the initial protection mechanism.","method":"BUB1-null MEF complementation assay, immunofluorescence, kinase-dead Bub1 expression, cell cycle staging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean null complementation assay with staged localization analysis; single lab, two orthogonal methods","pmids":["20124418"],"is_preprint":false},{"year":2011,"finding":"HP1α is targeted to mitotic centromeres by INCENP (a CPC subunit), not by SGO1. Both HP1-INCENP and HP1-SGO1 interactions require the HP1 chromo shadow domain binding to PXVXL/I motifs. An SGO1 mutant deficient in HP1 binding is fully functional in centromeric cohesion protection and localizes normally to centromeres in mitosis. HP1 binding by SGO1 is required for interphase centromere localization but dispensable for mitotic cohesion protection.","method":"Biochemical and structural analysis, mutagenesis, complementation assay, immunofluorescence in human cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structural analysis plus mutagenesis with functional cell-based validation; multiple orthogonal methods in single study","pmids":["21346195"],"is_preprint":false},{"year":2011,"finding":"In budding yeast, overexpression of SGO1 partially corrects chromosome segregation defects of bub1Δ cells and restores viability to bub1Δ tetraploid cells. Overexpression of CPC subunits Bir1 (survivin) and Sli15 (INCENP) suppresses growth defects of both bub1Δ and sgo1Δ tetraploids. Sgo1 is identified as a possible partner of Mps1; Mps1 is required for Sgo1 kinetochore localization, and Sgo1 overexpression rescues Mps1 inactivation defects. The Bub1-Sgo1-Mps1 pathway acts independently of Aurora B for biorientation.","method":"High-copy suppressor screen, genetic epistasis, yeast genetics, overexpression rescue experiments","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — suppressor screen plus genetic epistasis; single lab, multiple genetic tests","pmids":["21389114"],"is_preprint":false},{"year":2014,"finding":"In budding yeast, Sgo1 recruits the PP2A isoform containing Rts1 to the pericentromeric region prior to biorientation. Artificial recruitment of Rts1 to a single chromosome is sufficient to perform the function of Sgo1 on that chromosome, establishing that a major function of Sgo1 is to recruit PP2A-Rts1. Sgo1 is also an APC/C substrate in yeast, with mitotic destruction depending on a D-box-related motif; however, removal from chromosomes before anaphase depends on tension-responsive mechanisms rather than degradation.","method":"Yeast genetics, artificial centromere targeting, epistasis, cell cycle analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — artificial recruitment sufficiency experiment plus genetic epistasis; mechanistically definitive approach","pmids":["25236599"],"is_preprint":false},{"year":2014,"finding":"Aurora B kinase interacts with and phosphorylates SGO1 in vitro and in vivo. Aurora B-mediated phosphorylation regulates the distribution of SGO1 between centromeres and chromosome arms. Expression of Aurora B kinase-dead mutant forms of SGO1 causes mislocalization from centromeres to chromosome arms.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant expression, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus cell-based localization with phospho-mutants; single lab, two orthogonal methods","pmids":["25451264"],"is_preprint":false},{"year":2022,"finding":"Using an integrative structure-function approach, the 'histone H3-like' SGO1 N-terminal tail interaction with the Survivin BIR domain was identified as the hotspot essential for CPC-SGO1 assembly, with downstream SGO1 residues and Borealin contributing to high-affinity binding. Disrupting the SGO1-Survivin interaction abolishes CPC-SGO1 assembly and perturbs CPC centromere localization and function. SGO1 and H3T3ph use the same surface on Survivin to bind CPC.","method":"Structural analysis, mutagenesis, co-immunoprecipitation, functional assays in human cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — integrative structural and biochemical approach with mutagenesis and functional validation; multiple orthogonal methods","pmids":["35776132"],"is_preprint":false},{"year":2018,"finding":"Budding yeast CENP-A (Cse4) interacts with SGO1 in vivo and in vitro. The N-terminus coiled-coil domain of Sgo1 (without the C-terminus) is sufficient for interaction with CENP-A and association with core centromeric (CEN) but not pericentric chromatin in a cell cycle-dependent manner. Depletion of CENP-A results in loss of Sgo1 from centromeric chromatin. The N-terminus is required for genome stability.","method":"Co-immunoprecipitation in vivo and in vitro, domain deletion analysis, ChIP, chromosome loss assay in S. cerevisiae","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro Co-IP plus ChIP with functional genomic stability readout; single lab, multiple methods","pmids":["28980861"],"is_preprint":false},{"year":2020,"finding":"SGO1 interacts directly with the dimerization domain of the CPC subunit Borealin in Xenopus egg extracts. Borealin and PP2A can bind simultaneously to the coiled-coil domain of SGO1. A Borealin mutant that disrupts SGO1-Borealin interaction causes defects in CPC chromosomal recruitment and Aurora B-dependent spindle assembly but not in spindle assembly checkpoint signaling at unattached kinetochores.","method":"Xenopus egg extract biochemical reconstitution, direct binding assay, mutagenesis, immunodepletion, functional assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution in cell-free system with mutagenesis and functional validation; multiple orthogonal methods","pmids":["32697622"],"is_preprint":false},{"year":2016,"finding":"In budding yeast, the Bub1-H2A-Sgo1-PP2A-Rts1 axis prevents premature silencing of the spindle assembly checkpoint prior to tension generation. Mutation of Bub1's kinase domain, the Bub1 phosphorylation site in H2A, or sgo1 mutants with abolished binding to H2A or PP2A-Rts1 all result in premature SAC silencing in the presence of tensionless attachment.","method":"Genetic epistasis, yeast mutant analysis, checkpoint assays in S. cerevisiae","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic epistasis with multiple defined mutants; single lab, convergent genetic evidence","pmids":["28040741"],"is_preprint":false},{"year":2019,"finding":"SET directly binds to a domain in SGO1 in close proximity to the cohesin-binding motif. SET disrupts SGO1-cohesin binding in a dose-dependent manner in vitro and by SET overexpression in cells. SET binding-deficient SGO1 mutant fully supports centromeric cohesion but delays chromosome segregation. SET depletion delays cohesion fatigue, and overexpression exacerbates it. Thus, SET functions during mitosis by disrupting the SGO1-cohesin interaction to promote timely chromosome segregation.","method":"In vitro binding assay, co-immunoprecipitation, mutagenesis, overexpression/depletion, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding reconstitution plus mutagenesis with functional cell-based readout; multiple orthogonal methods in single study","pmids":["31227592"],"is_preprint":false},{"year":2024,"finding":"CENP-A interacts with SGO1 and determines the localization of SGO1 to the centromere during mitosis. Lysine and arginine residues in the C-terminal domain of SGO1 are critical for CENP-A binding. Replacement of these basic residues with acidic residues perturbs localization of SGO1 and Aurora B to the centromere, resulting in aberrant chromosome segregation and premature chromatid separation.","method":"Co-immunoprecipitation, site-directed mutagenesis, immunofluorescence in human cells, functional chromosome segregation assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and functional localization/segregation readout; single lab, two orthogonal methods","pmids":["37777834"],"is_preprint":false},{"year":2016,"finding":"In budding yeast, Bub1 and Sgo1 act as a rheostat to regulate pericentric chromatin structure. Histone H2A phosphorylation by Bub1 and subsequent Sgo1 recruitment softens the chromatin spring in response to changes in microtubule dynamics. In response to reduced microtubule dynamics, a Bub1/Sgo1-dependent structural change causes contraction of inner kinetochore clusters and radial expansion of pericentric chromatin, with the pericentric chromatin becoming less dynamic.","method":"Live-cell imaging, fluorescence imaging, genetic analysis in S. cerevisiae, quantitative chromatin dynamics measurements","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with functional genetic dissection; single lab, quantitative mechanistic readout","pmids":["22365852"],"is_preprint":false},{"year":2006,"finding":"Two major isoforms of human SGO1 exhibit distinct subcellular localization: the longer isoform localizes to kinetochores during G2 through mitosis, while the short isoform (sSgo1, lacking exon 6) does not localize to kinetochores but enriches at mitotic spindles and is found at S-phase foci (some colocalizing with kinetochores). These different localizations suggest isoform-specific functions during the cell cycle.","method":"GFP fusion localization, live-cell imaging, co-localization with CREST antigen","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct GFP localization experiment with multiple time points; single lab but systematic isoform comparison","pmids":["16582621"],"is_preprint":false},{"year":2016,"finding":"In Xenopus cell-free system, both CENP-C and CENP-T can independently drive centromeric accumulation of SGO1 through recruitment of Bub1 to the KMN network. Mps1 is also required for this pathway. Forced targeting of Bub1 to centromeres (in the absence of other kinetochore components) is sufficient to restore SGO1 localization, demonstrating that Bub1-mediated H2A phosphorylation is the critical downstream signal.","method":"Xenopus egg cell-free system, immunodepletion, artificial targeting experiments, immunofluorescence","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — cell-free reconstitution with artificial targeting sufficiency experiment; mechanistically definitive approach","pmids":["27116032"],"is_preprint":false},{"year":2014,"finding":"A homozygous founder mutation in SGOL1 (K23E) causes CAID syndrome. Cultured fibroblasts from affected individuals showed accelerated cell cycle progression, higher senescence rate, and enhanced TGF-β signaling. Karyotypes showed centromeric cohesion defect (railroad appearance). Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the human abnormalities including defects in enteric nervous system and smooth muscle.","method":"Human genetics, cell biological analysis of patient fibroblasts, zebrafish morpholino knockdown, karyotyping","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human mutation identification with cellular phenotyping and zebrafish model validation; two orthogonal systems but no direct molecular mechanism of the K23E mutation established","pmids":["25282101"],"is_preprint":false},{"year":2012,"finding":"In budding yeast, Bub1 kinase activity is not required for spindle checkpoint function but is required for centromeric localization of Sgo1. Despite absence of centromeric Sgo1 in mitotic cells lacking Bub1 kinase activity, centromeric cohesion is still maintained until anaphase (negative result: Bub1 kinase-dependent Sgo1 centromeric localization in mitosis is not required to maintain cohesion).","method":"Bub1 kinase-dead MEF complementation, immunofluorescence, functional cohesion assays","journal":"Journal of cell science (duplicate entry under PMID 20124418)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean null complementation with kinase-dead rescue; mechanistically informative negative result with functional readout","pmids":["20124418"],"is_preprint":false}],"current_model":"SGO1 (Shugoshin 1) is a centromeric adaptor protein that protects centromeric cohesin during mitosis and meiosis by directly binding to cohesin (activated by CDK-mediated phosphorylation of SGO1), recruiting and positioning protein phosphatase 2A (PP2A), which dephosphorylates sororin to prevent WAPL-mediated cohesin removal; SGO1 centromeric localization is established in G2 via HP1 and in mitosis via Bub1-mediated histone H2A-T120 phosphorylation, with additional interactions with CENP-A, the CPC (via Survivin and Borealin subunits), and Mps1 kinase enabling its roles in tension sensing, chromosome biorientation, and spindle checkpoint maintenance, while its small splice variant (sSgo1) functions independently at centrioles to maintain centriole cohesion in a Plk1-regulated manner, and SGO1 is ultimately degraded at mitotic exit by APC/C-Cdh1 through KEN box and D-box motifs."},"narrative":{"mechanistic_narrative":"SGO1 (Shugoshin 1) is a centromeric adaptor protein that protects centromeric cohesin during mitosis and meiosis and enforces accurate chromosome biorientation [PMID:15637284, PMID:16357219, PMID:23242214]. Its core protective function is to recruit and position protein phosphatase 2A (PP2A): SGO1 binds PP2A directly, and this interaction is required for SGO1's own centromeric residence [PMID:16580887], while in budding yeast artificial tethering of the PP2A-Rts1 isoform is sufficient to substitute for Sgo1 on a chromosome [PMID:25236599]. CDK-mediated mitosis-specific phosphorylation activates SGO1 to bind a cohesin complex containing PP2A, PDS5, and hypophosphorylated sororin but lacking WAPL, where SGO1-PP2A dephosphorylates PDS5-bound sororin to shield centromeric cohesin from WAPL-mediated removal [PMID:23242214]. SGO1 is targeted to centromeres through layered cues: HP1-dependent recruitment to centromeric heterochromatin in G2 [PMID:20124418, PMID:21346195], a kinetochore pool established by reading the Bub1-deposited histone H2A-pT120 mark [PMID:24055156, PMID:27116032], and CENP-A binding via basic C-terminal residues that anchors SGO1 and Aurora B at the centromere [PMID:37777834, PMID:28980861]. These distinct pools — a cohesin-bound inner-centromere pool and an H2A-pT120-bound kinetochore pool — are redistributed in response to kinetochore tension to couple cohesion protection to biorientation [PMID:24055156]. SGO1 additionally scaffolds the chromosomal passenger complex, binding the Survivin BIR domain through its histone-H3-like N-terminal tail and the Borealin dimerization domain to drive CPC centromere localization and Aurora B function [PMID:35776132, PMID:32697622]. Its activity is tuned by phosphorylation (NEK2A, Aurora B) [PMID:17621308, PMID:25451264] and antagonized by SET, which disrupts the SGO1-cohesin interaction to permit timely segregation [PMID:31227592], and SGO1 is degraded at mitotic exit by APC/C-Cdh1 acting on its KEN box and D-box [PMID:19015261]. A homozygous SGOL1 K23E founder mutation causes CAID syndrome, with patient cells showing centromeric cohesion defects and the phenotype recapitulated by zebrafish knockdown [PMID:25282101].","teleology":[{"year":2005,"claim":"Established that Sgo1 is required not for sensing microtubule occupancy but specifically for sensing tension at kinetochores and for sister-chromatid biorientation, defining its central role in chromosome segregation fidelity.","evidence":"Genetic mutant analysis with spindle checkpoint and segregation assays in S. cerevisiae","pmids":["15637284"],"confidence":"High","gaps":["Molecular basis of how Sgo1 transduces tension was not defined","Did not identify the cohesin-protection biochemistry in human cells"]},{"year":2005,"claim":"Mapped the meiotic Sgo1-binding domain to a 50-kb pericentric region where cohesins are protected, and showed its establishment depends on the core centromere, Bub1, and Spo13.","evidence":"ChIP domain mapping and genetic epistasis in S. cerevisiae meiosis","pmids":["16357219"],"confidence":"High","gaps":["Did not establish the protective enzymatic mechanism","Meiosis-specific factors may not generalize to mitosis or mammals"]},{"year":2006,"claim":"Identified PP2A as a direct SGO1 partner and showed the interaction is mutually required for centromeric localization, counteracting Plk1-mediated removal, establishing the SGO1-PP2A axis as the effector of cohesion protection.","evidence":"Reciprocal Co-IP, RNAi epistasis, and immunofluorescence in human cells","pmids":["16580887"],"confidence":"High","gaps":["Did not show how PP2A protects cohesin biochemically","Substrate of the recruited phosphatase not yet identified"]},{"year":2006,"claim":"Distinguished two human SGO1 isoforms with separable localizations, foreshadowing isoform-specific functions at kinetochores versus spindles/centrosomes.","evidence":"GFP-fusion live-cell imaging and CREST co-localization in human cells","pmids":["16582621"],"confidence":"Medium","gaps":["Functional consequences of isoform localization not tested here","Single-lab localization without functional perturbation"]},{"year":2007,"claim":"Showed NEK2A directly phosphorylates SGO1 at defined sites to support chromosome congression and correct attachment, adding a kinase regulatory input distinct from kinetochore assembly.","evidence":"In vitro kinase assay with site mapping and phospho-mutant imaging","pmids":["17621308"],"confidence":"High","gaps":["How phosphorylation alters SGO1 partner binding not resolved","Phosphorylation dispensable for kinetochore assembly, leaving its precise role partial"]},{"year":2008,"claim":"Defined the short splice variant sSgo1 as a centrosome/spindle-pole protein that maintains centriole cohesion through a Plk1-regulated mechanism, separating a non-cohesin SGO1 function.","evidence":"GFP localization, reciprocal Co-IP, RNAi rescue, and Plk1 epistasis in human cells","pmids":["18331714"],"confidence":"High","gaps":["Molecular mechanism of centriole cohesion by sSgo1 not detailed","Relationship between sSgo1 and full-length cohesin protection unclear"]},{"year":2008,"claim":"Identified SGO1 as an APC/C-Cdh1 substrate requiring both KEN box and D-box for degradation, but showed degradation is dispensable for mitotic progression, clarifying that turnover is regulatory rather than essential for segregation.","evidence":"In vitro ubiquitination, degron mutagenesis, and cell-cycle synchronization in human cells","pmids":["19015261"],"confidence":"High","gaps":["Functional purpose of SGO1 degradation not established","Bub1-dependent steady-state control mechanism left undefined"]},{"year":2009,"claim":"Demonstrated biochemically that Sgo1 stabilizes arm cohesin in prophase and that Plk1 and Aurora B antagonize this to drive sister resolution, placing SGO1 within the prophase pathway.","evidence":"Xenopus egg extract reconstitution with immunodepletion and rescue","pmids":["19696148"],"confidence":"High","gaps":["Direct substrate of the antagonizing kinases on SGO1 not mapped","Single cell-free system"]},{"year":2010,"claim":"Resolved the temporal recruitment logic by showing G2 centromeric loading is HP1-dependent and Bub1-kinase-independent, and that this early pool, not the mitotic Bub1-dependent pool, suffices to establish cohesion protection.","evidence":"BUB1-null/kinase-dead MEF complementation with staged immunofluorescence","pmids":["20124418"],"confidence":"Medium","gaps":["Why mitotic centromeric SGO1 is dispensable for cohesion not mechanistically explained","Single lab"]},{"year":2011,"claim":"Separated SGO1's HP1- and CPC-dependent localization modes, showing HP1 binding governs interphase localization but is dispensable for mitotic cohesion protection.","evidence":"Structural/biochemical analysis, mutagenesis, and complementation in human cells","pmids":["21346195"],"confidence":"High","gaps":["Determinants of mitotic centromere targeting independent of HP1 not fully enumerated here"]},{"year":2011,"claim":"Genetically positioned Sgo1 within a Bub1-Sgo1-Mps1 biorientation pathway acting in parallel to Aurora B, with Mps1 required for Sgo1 kinetochore localization.","evidence":"High-copy suppressor screen and genetic epistasis in S. cerevisiae","pmids":["21389114"],"confidence":"Medium","gaps":["Direct biochemical Mps1-Sgo1 interaction not demonstrated","Genetic-only evidence"]},{"year":2012,"claim":"Defined the activating switch: CDK-mediated mitotic phosphorylation enables SGO1 to bind a WAPL-free cohesin complex, where SGO1-PP2A dephosphorylates PDS5-bound sororin to protect centromeric cohesin.","evidence":"In vitro kinase/binding assays, RNAi, and non-phosphorylatable sororin rescue in human cells","pmids":["23242214"],"confidence":"High","gaps":["Structural basis of the phospho-dependent cohesin engagement not resolved","How tension reverses this protection not addressed here"]},{"year":2013,"claim":"Distinguished two mechanistically separate SGO1-PP2A pools (inner-centromere cohesin-bound and kinetochore H2A-pT120-bound) and showed tension drives their redistribution, linking cohesion protection to faithful segregation.","evidence":"RNAi, phospho-mutant expression, and tension perturbation with imaging in human cells","pmids":["24055156"],"confidence":"High","gaps":["Signal coupling tension to SGO1 dephosphorylation not molecularly defined"]},{"year":2014,"claim":"Established by artificial-tethering sufficiency that a principal function of Sgo1 is to recruit PP2A-Rts1 to pericentromeres, and clarified that pre-anaphase chromosomal removal is tension-driven rather than degradation-driven.","evidence":"Artificial centromere targeting and genetic epistasis in S. cerevisiae","pmids":["25236599"],"confidence":"High","gaps":["Whether PP2A recruitment is fully sufficient in mammalian cells not tested here"]},{"year":2014,"claim":"Extended Sgo1's biorientation role beyond cohesin protection, showing it directs condensin to centromeric chromatin and maintains Aurora B/Ipl1 at kinetochores.","evidence":"Genetic epistasis and ChIP in S. cerevisiae","pmids":["24945276"],"confidence":"Medium","gaps":["Direct Sgo1-condensin interaction not demonstrated","Mammalian relevance untested"]},{"year":2014,"claim":"Identified Aurora B as a kinase that phosphorylates SGO1 to control its partition between centromeres and chromosome arms.","evidence":"Co-IP, in vitro kinase assay, and phospho-mutant localization in human cells","pmids":["25451264"],"confidence":"Medium","gaps":["Functional consequence for cohesion vs biorientation not separated","Phospho-sites not detailed in this entry"]},{"year":2014,"claim":"Linked SGOL1 to human disease by identifying the K23E founder mutation causing CAID syndrome, with patient cells showing centromeric cohesion defects and zebrafish phenocopy.","evidence":"Human genetics, patient fibroblast phenotyping, and zebrafish morpholino knockdown","pmids":["25282101"],"confidence":"Medium","gaps":["Molecular mechanism by which K23E impairs SGO1 function not established","Connection between cohesion defect and enteric/smooth muscle phenotype unclear"]},{"year":2015,"claim":"Showed SGO1 directly reads the Bub1-dependent H2A-pT120 mark and that Bub1-driven mitotic transcription by Pol II is needed for kinetochore-bound SGO1 to access cohesin in centromeric chromatin.","evidence":"Co-IP, in vitro RNA-binding, Pol II inactivation, and ChIP in human cells","pmids":["26190260"],"confidence":"High","gaps":["How transcription physically delivers SGO1 to cohesin not resolved","RNA partner identity undefined"]},{"year":2016,"claim":"Demonstrated that CENP-C and CENP-T independently route SGO1 to centromeres via Bub1 recruitment, and that forced centromeric Bub1 alone restores SGO1 localization, identifying H2A phosphorylation as the convergent signal.","evidence":"Xenopus cell-free reconstitution with immunodepletion and artificial targeting","pmids":["27116032"],"confidence":"High","gaps":["Quantitative contribution of each inner-kinetochore arm not parsed"]},{"year":2016,"claim":"Showed the Bub1-H2A-Sgo1-PP2A-Rts1 axis prevents premature spindle checkpoint silencing before tension is generated, coupling SGO1 to checkpoint timing.","evidence":"Systematic genetic epistasis with defined mutants in S. cerevisiae","pmids":["28040741"],"confidence":"Medium","gaps":["Direct checkpoint substrate of the axis not identified","Yeast-specific"]},{"year":2016,"claim":"Defined a structural role for the Bub1/Sgo1 module as a rheostat reshaping pericentric chromatin in response to microtubule dynamics.","evidence":"Quantitative live-cell imaging and genetics in S. cerevisiae","pmids":["22365852"],"confidence":"Medium","gaps":["Mechanism connecting chromatin spring changes to cohesion not established","Mammalian conservation untested"]},{"year":2018,"claim":"Identified CENP-A as a Sgo1 interactor in yeast, with the Sgo1 N-terminal coiled-coil sufficient for CENP-A binding and core-centromere association required for genome stability.","evidence":"In vivo/in vitro Co-IP, domain deletion, ChIP, and chromosome loss assays in S. cerevisiae","pmids":["28980861"],"confidence":"Medium","gaps":["Whether CENP-A binding is direct vs bridged not fully resolved","Single lab"]},{"year":2019,"claim":"Defined SET as a direct negative regulator that disrupts the SGO1-cohesin interaction to enable timely segregation, identifying an antagonist of cohesion protection.","evidence":"In vitro binding, mutagenesis, overexpression/depletion, and live-cell imaging in human cells","pmids":["31227592"],"confidence":"High","gaps":["How SET activity is regulated during the cell cycle not addressed"]},{"year":2020,"claim":"Showed SGO1 binds the Borealin dimerization domain directly and simultaneously with PP2A, and that this interaction drives CPC chromosomal recruitment and Aurora B-dependent spindle assembly but not SAC signaling.","evidence":"Xenopus egg extract reconstitution, direct binding, and mutagenesis","pmids":["32697622"],"confidence":"High","gaps":["Coordination between Borealin and Survivin contacts not fully integrated here"]},{"year":2022,"claim":"Defined the histone-H3-like SGO1 N-terminal tail-Survivin BIR domain interaction as the essential hotspot for CPC-SGO1 assembly, with SGO1 and H3T3ph competing for the same Survivin surface.","evidence":"Integrative structure-function analysis, mutagenesis, and Co-IP in human cells","pmids":["35776132"],"confidence":"High","gaps":["How competition with H3T3ph is regulated in time/space not resolved"]},{"year":2024,"claim":"Established in human cells that basic C-terminal SGO1 residues mediate CENP-A binding and that this interaction determines SGO1 and Aurora B centromere localization and segregation fidelity.","evidence":"Co-IP, site-directed charge-reversal mutagenesis, and segregation assays in human cells","pmids":["37777834"],"confidence":"Medium","gaps":["Whether CENP-A binding is direct not fully resolved","Single lab"]},{"year":null,"claim":"The molecular signal that couples kinetochore tension to SGO1 dephosphorylation and redistribution, and the mechanism by which the CAID-causing K23E substitution disrupts SGO1 function, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of tension-driven SGO1 conformational/positional change","No mechanistic explanation of K23E pathogenicity","Identity of the SGO1-associated RNA enabling cohesin access undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,16,18,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,11,24]},{"term_id":"GO:0003723","term_label":"RNA 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BIOGENESIS REGULATOR 1 HOMOLOG; RRS1","url":"https://www.omim.org/entry/618311"},{"mim_id":"614560","title":"MAU2 SISTER CHROMATID COHESION FACTOR; MAU2","url":"https://www.omim.org/entry/614560"},{"mim_id":"612425","title":"SHUGOSHIN-LIKE 2; SGOL2","url":"https://www.omim.org/entry/612425"},{"mim_id":"609374","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 5; CDCA5","url":"https://www.omim.org/entry/609374"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Kinetochore","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":8.2},{"tissue":"lymphoid 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meiosis","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677360","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.22.677724","title":"Shugoshin holds the potential to inhibit APC/C and thereby prevents separase activation","date":"2025-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.677724","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.01.662622","title":"Cell enlargement causes mitotic errors and aneuploidy in cells that evade senescence after CDK4/6 inhibition","date":"2025-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.01.662622","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.03.601947","title":"Dynamic Plk1 recruitment to the inner centromere","date":"2024-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.03.601947","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.19.671082","title":"Monopolar orientation of kinetochores at meiosis is enforced by COHESINS and their regulators, CENP-C, and the deSUMOylase SPF2","date":"2025-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.671082","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.18.654701","title":"Engineering precision zebrafish alleles of human disease","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.18.654701","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29839,"output_tokens":7284,"usd":0.099389,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16417,"output_tokens":6916,"usd":0.127493,"stage2_stop_reason":"end_turn"},"total_usd":0.226882,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Human SGO1 directly binds to protein phosphatase 2A (PP2A). PP2A localizes to centromeres in a Bub1-dependent manner, and the SGO1-PP2A interaction is required for centromeric localization of SGO1. Depletion of Plk1 by RNAi restores centromeric SGO1 localization in PP2A-depleted cells, indicating that Bub1 targets PP2A to centromeres which counteracts Plk1-mediated removal of SGO1.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, immunofluorescence localization, epistasis analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi epistasis with multiple orthogonal methods; widely replicated by subsequent studies\",\n      \"pmids\": [\"16580887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDK-mediated mitosis-specific phosphorylation of SGO1 activates its cohesion-protection function and enables direct binding of SGO1 to cohesin. The phospho-SGO1-bound cohesin complex contains PP2A, PDS5, and hypophosphorylated sororin, but lacks WAPL. SGO1-PP2A dephosphorylates PDS5-bound sororin, protecting centromeric cohesin from WAPL. Expression of non-phosphorylatable sororin bypasses the requirement for SGO1-PP2A in centromeric cohesion.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, RNAi, phospho-mutant expression, rescue experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods including in vitro binding assays and genetic rescue in single rigorous study\",\n      \"pmids\": [\"23242214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SGO1 is a direct reader of the Bub1-mediated histone H2A-pT120 mark. Bub1 recruits RNA Polymerase II (Pol II) to unattached kinetochores, promoting mitotic transcription. Mitosis-specific inactivation of Pol II traps SGO1 at kinetochores and weakens centromeric cohesion. SGO1 interacts with Pol II in human cells and with RNA in vitro, suggesting Pol II-dependent transcription enables kinetochore-bound SGO1 to reach cohesin embedded in centromeric chromatin.\",\n      \"method\": \"Co-immunoprecipitation, RNA-binding assay in vitro, Pol II inactivation, immunofluorescence, ChIP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro RNA binding, Pol II inhibition with functional readout) in a single rigorous study\",\n      \"pmids\": [\"26190260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cohesin and histone H2A-pT120 specify two distinct pools of SGO1-PP2A: one at inner centromeres (cohesin-bound) and one at kinetochores (H2A-pT120-bound). Bub1 inactivation delocalizes cohesin-SGO1 to chromosome arms. Kinetochore tension triggers SGO1 dephosphorylation and redistributes SGO1 from inner centromeres to kinetochores; incomplete redistribution causes chromosome nondisjunction.\",\n      \"method\": \"RNAi, phospho-mutant expression, immunofluorescence, tension perturbation experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, phospho-mutants, functional epistasis) establishing two mechanistically distinct SGO1 pools\",\n      \"pmids\": [\"24055156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Budding yeast Sgo1 is required for sensing lack of tension at the kinetochore in mitosis. SGO1 mutant cells respond normally to microtubule depolymerization but fail to respond to lack of tension, and have difficulty attaching sister chromatids to opposite poles (biorientation defect). Degradation of Sgo1 when sister chromatids separate prevents cell cycle arrest in anaphase.\",\n      \"method\": \"Genetic mutant analysis, spindle checkpoint assays, chromosome segregation assays in S. cerevisiae\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific mechanistic phenotypic readout; foundational paper replicated extensively\",\n      \"pmids\": [\"15637284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Xenopus egg extract reconstitution, Sgo1 plays a role in stabilizing cohesin along chromosome arms during prophase. This stabilizing activity is antagonized by the mitotic kinases Plk1 and Aurora B, which promotes sister chromatid resolution.\",\n      \"method\": \"Xenopus egg extract in vitro reconstitution, immunodepletion, functional rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in cell-free system with depletion/rescue; single lab but rigorous biochemical approach\",\n      \"pmids\": [\"19696148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The short splice variant of SGO1 (sSgo1) localizes to the centrosome in interphase and to spindle poles in mitosis. sSgo1 interacts with Plk1, and its spindle pole localization is Plk1-dependent. sSgo1 is required for centriole cohesion; its depletion causes separation of paired centrioles, and this can be suppressed by sSgo1 re-expression or Plk1 knockdown.\",\n      \"method\": \"GFP localization, co-immunoprecipitation, RNAi, dominant-negative mutant expression, centrosome imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiment and epistasis with Plk1; multiple orthogonal approaches\",\n      \"pmids\": [\"18331714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NEK2A directly binds human SGO1 in vitro and co-localizes with SGO1 at kinetochores. NEK2A phosphorylates SGO1 at Ser14 and Ser507. Non-phosphorylatable SGO1 mutants perturb chromosome congression and cause increased microtubule attachment errors (syntelic and monotelic attachments), though phosphorylation is not required for SGO1 assembly at kinetochores.\",\n      \"method\": \"In vitro pulldown, in vitro phosphorylation assay with 32P incorporation, phospho-site mapping, expression of phospho-mutants, immunofluorescence\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with site mapping plus functional phospho-mutant analysis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"17621308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In budding yeast, Sgo1 together with PP2A-Rts1 ensures localization of condensin to centromeric chromatin. Sgo1 is also required for maintaining Aurora B/Ipl1 localization on kinetochores during metaphase. Thus Sgo1 has a dual function in promoting chromosome biorientation: modulating pericentric chromatin conformation via condensin, and maintaining Aurora B/Ipl1 at kinetochores.\",\n      \"method\": \"Genetic epistasis, chromatin immunoprecipitation (ChIP), immunofluorescence, yeast genetics\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and ChIP in S. cerevisiae, two orthogonal methods, single lab\",\n      \"pmids\": [\"24945276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human SGO1 is degraded during mitotic exit and is a substrate of APC/C-Cdh1. SGO1 contains both a KEN box and a D-box; deletion of either motif alone is insufficient to stabilize SGO1, but simultaneous deletion of both renders it stable. Non-degradable SGO1 does not impair mitotic progression or sister-chromatid separation, indicating SGO1 degradation is not required for these processes. Bub1 contributes to SGO1 steady-state levels via an APC/C-independent mechanism.\",\n      \"method\": \"Ubiquitination assay in vitro, overexpression/knockdown, deletion mutagenesis, cell cycle synchronization, western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assay plus mutagenesis of degradation motifs with functional cell-based validation; multiple orthogonal methods\",\n      \"pmids\": [\"19015261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In budding yeast, Sgo1 localizes to cohesin-associated regions (CARs) at the centromere and a 50-kb pericentric domain during meiosis I. Establishment of this domain requires the 120-bp core centromere, Bub1, and the meiosis-specific factor Spo13. Cohesins and kinetochore proteins Iml3/Chl4 are necessary for Sgo1 to associate with pericentric but not core centromeric regions. This 50-kb Sgo1-binding domain is where cohesins are protected from removal during meiosis I.\",\n      \"method\": \"ChIP, genetic epistasis, localization studies in S. cerevisiae meiosis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-based domain mapping with systematic genetic epistasis; replicated across multiple mutant backgrounds\",\n      \"pmids\": [\"16357219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SGO1 is first recruited to centromeric heterochromatin in G2 in an HP1-dependent manner that does not require Bub1 kinase activity. In prophase, SGO1 becomes diffusely localized, then returns to centromeres in a Bub1 kinase-dependent manner. Despite the absence of SGO1 from mitotic centromeres when Bub1 kinase is absent, centromeric cohesion is maintained, suggesting the G2 recruitment establishes the initial protection mechanism.\",\n      \"method\": \"BUB1-null MEF complementation assay, immunofluorescence, kinase-dead Bub1 expression, cell cycle staging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean null complementation assay with staged localization analysis; single lab, two orthogonal methods\",\n      \"pmids\": [\"20124418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HP1α is targeted to mitotic centromeres by INCENP (a CPC subunit), not by SGO1. Both HP1-INCENP and HP1-SGO1 interactions require the HP1 chromo shadow domain binding to PXVXL/I motifs. An SGO1 mutant deficient in HP1 binding is fully functional in centromeric cohesion protection and localizes normally to centromeres in mitosis. HP1 binding by SGO1 is required for interphase centromere localization but dispensable for mitotic cohesion protection.\",\n      \"method\": \"Biochemical and structural analysis, mutagenesis, complementation assay, immunofluorescence in human cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural analysis plus mutagenesis with functional cell-based validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21346195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In budding yeast, overexpression of SGO1 partially corrects chromosome segregation defects of bub1Δ cells and restores viability to bub1Δ tetraploid cells. Overexpression of CPC subunits Bir1 (survivin) and Sli15 (INCENP) suppresses growth defects of both bub1Δ and sgo1Δ tetraploids. Sgo1 is identified as a possible partner of Mps1; Mps1 is required for Sgo1 kinetochore localization, and Sgo1 overexpression rescues Mps1 inactivation defects. The Bub1-Sgo1-Mps1 pathway acts independently of Aurora B for biorientation.\",\n      \"method\": \"High-copy suppressor screen, genetic epistasis, yeast genetics, overexpression rescue experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — suppressor screen plus genetic epistasis; single lab, multiple genetic tests\",\n      \"pmids\": [\"21389114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In budding yeast, Sgo1 recruits the PP2A isoform containing Rts1 to the pericentromeric region prior to biorientation. Artificial recruitment of Rts1 to a single chromosome is sufficient to perform the function of Sgo1 on that chromosome, establishing that a major function of Sgo1 is to recruit PP2A-Rts1. Sgo1 is also an APC/C substrate in yeast, with mitotic destruction depending on a D-box-related motif; however, removal from chromosomes before anaphase depends on tension-responsive mechanisms rather than degradation.\",\n      \"method\": \"Yeast genetics, artificial centromere targeting, epistasis, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — artificial recruitment sufficiency experiment plus genetic epistasis; mechanistically definitive approach\",\n      \"pmids\": [\"25236599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Aurora B kinase interacts with and phosphorylates SGO1 in vitro and in vivo. Aurora B-mediated phosphorylation regulates the distribution of SGO1 between centromeres and chromosome arms. Expression of Aurora B kinase-dead mutant forms of SGO1 causes mislocalization from centromeres to chromosome arms.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant expression, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus cell-based localization with phospho-mutants; single lab, two orthogonal methods\",\n      \"pmids\": [\"25451264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using an integrative structure-function approach, the 'histone H3-like' SGO1 N-terminal tail interaction with the Survivin BIR domain was identified as the hotspot essential for CPC-SGO1 assembly, with downstream SGO1 residues and Borealin contributing to high-affinity binding. Disrupting the SGO1-Survivin interaction abolishes CPC-SGO1 assembly and perturbs CPC centromere localization and function. SGO1 and H3T3ph use the same surface on Survivin to bind CPC.\",\n      \"method\": \"Structural analysis, mutagenesis, co-immunoprecipitation, functional assays in human cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — integrative structural and biochemical approach with mutagenesis and functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"35776132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Budding yeast CENP-A (Cse4) interacts with SGO1 in vivo and in vitro. The N-terminus coiled-coil domain of Sgo1 (without the C-terminus) is sufficient for interaction with CENP-A and association with core centromeric (CEN) but not pericentric chromatin in a cell cycle-dependent manner. Depletion of CENP-A results in loss of Sgo1 from centromeric chromatin. The N-terminus is required for genome stability.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro, domain deletion analysis, ChIP, chromosome loss assay in S. cerevisiae\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro Co-IP plus ChIP with functional genomic stability readout; single lab, multiple methods\",\n      \"pmids\": [\"28980861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SGO1 interacts directly with the dimerization domain of the CPC subunit Borealin in Xenopus egg extracts. Borealin and PP2A can bind simultaneously to the coiled-coil domain of SGO1. A Borealin mutant that disrupts SGO1-Borealin interaction causes defects in CPC chromosomal recruitment and Aurora B-dependent spindle assembly but not in spindle assembly checkpoint signaling at unattached kinetochores.\",\n      \"method\": \"Xenopus egg extract biochemical reconstitution, direct binding assay, mutagenesis, immunodepletion, functional assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution in cell-free system with mutagenesis and functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"32697622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In budding yeast, the Bub1-H2A-Sgo1-PP2A-Rts1 axis prevents premature silencing of the spindle assembly checkpoint prior to tension generation. Mutation of Bub1's kinase domain, the Bub1 phosphorylation site in H2A, or sgo1 mutants with abolished binding to H2A or PP2A-Rts1 all result in premature SAC silencing in the presence of tensionless attachment.\",\n      \"method\": \"Genetic epistasis, yeast mutant analysis, checkpoint assays in S. cerevisiae\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic epistasis with multiple defined mutants; single lab, convergent genetic evidence\",\n      \"pmids\": [\"28040741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SET directly binds to a domain in SGO1 in close proximity to the cohesin-binding motif. SET disrupts SGO1-cohesin binding in a dose-dependent manner in vitro and by SET overexpression in cells. SET binding-deficient SGO1 mutant fully supports centromeric cohesion but delays chromosome segregation. SET depletion delays cohesion fatigue, and overexpression exacerbates it. Thus, SET functions during mitosis by disrupting the SGO1-cohesin interaction to promote timely chromosome segregation.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, mutagenesis, overexpression/depletion, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding reconstitution plus mutagenesis with functional cell-based readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31227592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CENP-A interacts with SGO1 and determines the localization of SGO1 to the centromere during mitosis. Lysine and arginine residues in the C-terminal domain of SGO1 are critical for CENP-A binding. Replacement of these basic residues with acidic residues perturbs localization of SGO1 and Aurora B to the centromere, resulting in aberrant chromosome segregation and premature chromatid separation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, immunofluorescence in human cells, functional chromosome segregation assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and functional localization/segregation readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"37777834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In budding yeast, Bub1 and Sgo1 act as a rheostat to regulate pericentric chromatin structure. Histone H2A phosphorylation by Bub1 and subsequent Sgo1 recruitment softens the chromatin spring in response to changes in microtubule dynamics. In response to reduced microtubule dynamics, a Bub1/Sgo1-dependent structural change causes contraction of inner kinetochore clusters and radial expansion of pericentric chromatin, with the pericentric chromatin becoming less dynamic.\",\n      \"method\": \"Live-cell imaging, fluorescence imaging, genetic analysis in S. cerevisiae, quantitative chromatin dynamics measurements\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with functional genetic dissection; single lab, quantitative mechanistic readout\",\n      \"pmids\": [\"22365852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two major isoforms of human SGO1 exhibit distinct subcellular localization: the longer isoform localizes to kinetochores during G2 through mitosis, while the short isoform (sSgo1, lacking exon 6) does not localize to kinetochores but enriches at mitotic spindles and is found at S-phase foci (some colocalizing with kinetochores). These different localizations suggest isoform-specific functions during the cell cycle.\",\n      \"method\": \"GFP fusion localization, live-cell imaging, co-localization with CREST antigen\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct GFP localization experiment with multiple time points; single lab but systematic isoform comparison\",\n      \"pmids\": [\"16582621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus cell-free system, both CENP-C and CENP-T can independently drive centromeric accumulation of SGO1 through recruitment of Bub1 to the KMN network. Mps1 is also required for this pathway. Forced targeting of Bub1 to centromeres (in the absence of other kinetochore components) is sufficient to restore SGO1 localization, demonstrating that Bub1-mediated H2A phosphorylation is the critical downstream signal.\",\n      \"method\": \"Xenopus egg cell-free system, immunodepletion, artificial targeting experiments, immunofluorescence\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — cell-free reconstitution with artificial targeting sufficiency experiment; mechanistically definitive approach\",\n      \"pmids\": [\"27116032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous founder mutation in SGOL1 (K23E) causes CAID syndrome. Cultured fibroblasts from affected individuals showed accelerated cell cycle progression, higher senescence rate, and enhanced TGF-β signaling. Karyotypes showed centromeric cohesion defect (railroad appearance). Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the human abnormalities including defects in enteric nervous system and smooth muscle.\",\n      \"method\": \"Human genetics, cell biological analysis of patient fibroblasts, zebrafish morpholino knockdown, karyotyping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human mutation identification with cellular phenotyping and zebrafish model validation; two orthogonal systems but no direct molecular mechanism of the K23E mutation established\",\n      \"pmids\": [\"25282101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In budding yeast, Bub1 kinase activity is not required for spindle checkpoint function but is required for centromeric localization of Sgo1. Despite absence of centromeric Sgo1 in mitotic cells lacking Bub1 kinase activity, centromeric cohesion is still maintained until anaphase (negative result: Bub1 kinase-dependent Sgo1 centromeric localization in mitosis is not required to maintain cohesion).\",\n      \"method\": \"Bub1 kinase-dead MEF complementation, immunofluorescence, functional cohesion assays\",\n      \"journal\": \"Journal of cell science (duplicate entry under PMID 20124418)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean null complementation with kinase-dead rescue; mechanistically informative negative result with functional readout\",\n      \"pmids\": [\"20124418\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SGO1 (Shugoshin 1) is a centromeric adaptor protein that protects centromeric cohesin during mitosis and meiosis by directly binding to cohesin (activated by CDK-mediated phosphorylation of SGO1), recruiting and positioning protein phosphatase 2A (PP2A), which dephosphorylates sororin to prevent WAPL-mediated cohesin removal; SGO1 centromeric localization is established in G2 via HP1 and in mitosis via Bub1-mediated histone H2A-T120 phosphorylation, with additional interactions with CENP-A, the CPC (via Survivin and Borealin subunits), and Mps1 kinase enabling its roles in tension sensing, chromosome biorientation, and spindle checkpoint maintenance, while its small splice variant (sSgo1) functions independently at centrioles to maintain centriole cohesion in a Plk1-regulated manner, and SGO1 is ultimately degraded at mitotic exit by APC/C-Cdh1 through KEN box and D-box motifs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SGO1 (Shugoshin 1) is a centromeric adaptor protein that protects centromeric cohesin during mitosis and meiosis and enforces accurate chromosome biorientation [#4, #10, #1]. Its core protective function is to recruit and position protein phosphatase 2A (PP2A): SGO1 binds PP2A directly, and this interaction is required for SGO1's own centromeric residence [#0], while in budding yeast artificial tethering of the PP2A-Rts1 isoform is sufficient to substitute for Sgo1 on a chromosome [#14]. CDK-mediated mitosis-specific phosphorylation activates SGO1 to bind a cohesin complex containing PP2A, PDS5, and hypophosphorylated sororin but lacking WAPL, where SGO1-PP2A dephosphorylates PDS5-bound sororin to shield centromeric cohesin from WAPL-mediated removal [#1]. SGO1 is targeted to centromeres through layered cues: HP1-dependent recruitment to centromeric heterochromatin in G2 [#11, #12], a kinetochore pool established by reading the Bub1-deposited histone H2A-pT120 mark [#3, #24], and CENP-A binding via basic C-terminal residues that anchors SGO1 and Aurora B at the centromere [#21, #17]. These distinct pools — a cohesin-bound inner-centromere pool and an H2A-pT120-bound kinetochore pool — are redistributed in response to kinetochore tension to couple cohesion protection to biorientation [#3]. SGO1 additionally scaffolds the chromosomal passenger complex, binding the Survivin BIR domain through its histone-H3-like N-terminal tail and the Borealin dimerization domain to drive CPC centromere localization and Aurora B function [#16, #18]. Its activity is tuned by phosphorylation (NEK2A, Aurora B) [#7, #15] and antagonized by SET, which disrupts the SGO1-cohesin interaction to permit timely segregation [#20], and SGO1 is degraded at mitotic exit by APC/C-Cdh1 acting on its KEN box and D-box [#9]. A homozygous SGOL1 K23E founder mutation causes CAID syndrome, with patient cells showing centromeric cohesion defects and the phenotype recapitulated by zebrafish knockdown [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that Sgo1 is required not for sensing microtubule occupancy but specifically for sensing tension at kinetochores and for sister-chromatid biorientation, defining its central role in chromosome segregation fidelity.\",\n      \"evidence\": \"Genetic mutant analysis with spindle checkpoint and segregation assays in S. cerevisiae\",\n      \"pmids\": [\"15637284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of how Sgo1 transduces tension was not defined\", \"Did not identify the cohesin-protection biochemistry in human cells\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the meiotic Sgo1-binding domain to a 50-kb pericentric region where cohesins are protected, and showed its establishment depends on the core centromere, Bub1, and Spo13.\",\n      \"evidence\": \"ChIP domain mapping and genetic epistasis in S. cerevisiae meiosis\",\n      \"pmids\": [\"16357219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the protective enzymatic mechanism\", \"Meiosis-specific factors may not generalize to mitosis or mammals\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified PP2A as a direct SGO1 partner and showed the interaction is mutually required for centromeric localization, counteracting Plk1-mediated removal, establishing the SGO1-PP2A axis as the effector of cohesion protection.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi epistasis, and immunofluorescence in human cells\",\n      \"pmids\": [\"16580887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how PP2A protects cohesin biochemically\", \"Substrate of the recruited phosphatase not yet identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Distinguished two human SGO1 isoforms with separable localizations, foreshadowing isoform-specific functions at kinetochores versus spindles/centrosomes.\",\n      \"evidence\": \"GFP-fusion live-cell imaging and CREST co-localization in human cells\",\n      \"pmids\": [\"16582621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of isoform localization not tested here\", \"Single-lab localization without functional perturbation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed NEK2A directly phosphorylates SGO1 at defined sites to support chromosome congression and correct attachment, adding a kinase regulatory input distinct from kinetochore assembly.\",\n      \"evidence\": \"In vitro kinase assay with site mapping and phospho-mutant imaging\",\n      \"pmids\": [\"17621308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters SGO1 partner binding not resolved\", \"Phosphorylation dispensable for kinetochore assembly, leaving its precise role partial\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the short splice variant sSgo1 as a centrosome/spindle-pole protein that maintains centriole cohesion through a Plk1-regulated mechanism, separating a non-cohesin SGO1 function.\",\n      \"evidence\": \"GFP localization, reciprocal Co-IP, RNAi rescue, and Plk1 epistasis in human cells\",\n      \"pmids\": [\"18331714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of centriole cohesion by sSgo1 not detailed\", \"Relationship between sSgo1 and full-length cohesin protection unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified SGO1 as an APC/C-Cdh1 substrate requiring both KEN box and D-box for degradation, but showed degradation is dispensable for mitotic progression, clarifying that turnover is regulatory rather than essential for segregation.\",\n      \"evidence\": \"In vitro ubiquitination, degron mutagenesis, and cell-cycle synchronization in human cells\",\n      \"pmids\": [\"19015261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional purpose of SGO1 degradation not established\", \"Bub1-dependent steady-state control mechanism left undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated biochemically that Sgo1 stabilizes arm cohesin in prophase and that Plk1 and Aurora B antagonize this to drive sister resolution, placing SGO1 within the prophase pathway.\",\n      \"evidence\": \"Xenopus egg extract reconstitution with immunodepletion and rescue\",\n      \"pmids\": [\"19696148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate of the antagonizing kinases on SGO1 not mapped\", \"Single cell-free system\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the temporal recruitment logic by showing G2 centromeric loading is HP1-dependent and Bub1-kinase-independent, and that this early pool, not the mitotic Bub1-dependent pool, suffices to establish cohesion protection.\",\n      \"evidence\": \"BUB1-null/kinase-dead MEF complementation with staged immunofluorescence\",\n      \"pmids\": [\"20124418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why mitotic centromeric SGO1 is dispensable for cohesion not mechanistically explained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated SGO1's HP1- and CPC-dependent localization modes, showing HP1 binding governs interphase localization but is dispensable for mitotic cohesion protection.\",\n      \"evidence\": \"Structural/biochemical analysis, mutagenesis, and complementation in human cells\",\n      \"pmids\": [\"21346195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of mitotic centromere targeting independent of HP1 not fully enumerated here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetically positioned Sgo1 within a Bub1-Sgo1-Mps1 biorientation pathway acting in parallel to Aurora B, with Mps1 required for Sgo1 kinetochore localization.\",\n      \"evidence\": \"High-copy suppressor screen and genetic epistasis in S. cerevisiae\",\n      \"pmids\": [\"21389114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical Mps1-Sgo1 interaction not demonstrated\", \"Genetic-only evidence\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the activating switch: CDK-mediated mitotic phosphorylation enables SGO1 to bind a WAPL-free cohesin complex, where SGO1-PP2A dephosphorylates PDS5-bound sororin to protect centromeric cohesin.\",\n      \"evidence\": \"In vitro kinase/binding assays, RNAi, and non-phosphorylatable sororin rescue in human cells\",\n      \"pmids\": [\"23242214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the phospho-dependent cohesin engagement not resolved\", \"How tension reverses this protection not addressed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished two mechanistically separate SGO1-PP2A pools (inner-centromere cohesin-bound and kinetochore H2A-pT120-bound) and showed tension drives their redistribution, linking cohesion protection to faithful segregation.\",\n      \"evidence\": \"RNAi, phospho-mutant expression, and tension perturbation with imaging in human cells\",\n      \"pmids\": [\"24055156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal coupling tension to SGO1 dephosphorylation not molecularly defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established by artificial-tethering sufficiency that a principal function of Sgo1 is to recruit PP2A-Rts1 to pericentromeres, and clarified that pre-anaphase chromosomal removal is tension-driven rather than degradation-driven.\",\n      \"evidence\": \"Artificial centromere targeting and genetic epistasis in S. cerevisiae\",\n      \"pmids\": [\"25236599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PP2A recruitment is fully sufficient in mammalian cells not tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended Sgo1's biorientation role beyond cohesin protection, showing it directs condensin to centromeric chromatin and maintains Aurora B/Ipl1 at kinetochores.\",\n      \"evidence\": \"Genetic epistasis and ChIP in S. cerevisiae\",\n      \"pmids\": [\"24945276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Sgo1-condensin interaction not demonstrated\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Aurora B as a kinase that phosphorylates SGO1 to control its partition between centromeres and chromosome arms.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, and phospho-mutant localization in human cells\",\n      \"pmids\": [\"25451264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for cohesion vs biorientation not separated\", \"Phospho-sites not detailed in this entry\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SGOL1 to human disease by identifying the K23E founder mutation causing CAID syndrome, with patient cells showing centromeric cohesion defects and zebrafish phenocopy.\",\n      \"evidence\": \"Human genetics, patient fibroblast phenotyping, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"25282101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which K23E impairs SGO1 function not established\", \"Connection between cohesion defect and enteric/smooth muscle phenotype unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SGO1 directly reads the Bub1-dependent H2A-pT120 mark and that Bub1-driven mitotic transcription by Pol II is needed for kinetochore-bound SGO1 to access cohesin in centromeric chromatin.\",\n      \"evidence\": \"Co-IP, in vitro RNA-binding, Pol II inactivation, and ChIP in human cells\",\n      \"pmids\": [\"26190260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcription physically delivers SGO1 to cohesin not resolved\", \"RNA partner identity undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CENP-C and CENP-T independently route SGO1 to centromeres via Bub1 recruitment, and that forced centromeric Bub1 alone restores SGO1 localization, identifying H2A phosphorylation as the convergent signal.\",\n      \"evidence\": \"Xenopus cell-free reconstitution with immunodepletion and artificial targeting\",\n      \"pmids\": [\"27116032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each inner-kinetochore arm not parsed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the Bub1-H2A-Sgo1-PP2A-Rts1 axis prevents premature spindle checkpoint silencing before tension is generated, coupling SGO1 to checkpoint timing.\",\n      \"evidence\": \"Systematic genetic epistasis with defined mutants in S. cerevisiae\",\n      \"pmids\": [\"28040741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct checkpoint substrate of the axis not identified\", \"Yeast-specific\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a structural role for the Bub1/Sgo1 module as a rheostat reshaping pericentric chromatin in response to microtubule dynamics.\",\n      \"evidence\": \"Quantitative live-cell imaging and genetics in S. cerevisiae\",\n      \"pmids\": [\"22365852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting chromatin spring changes to cohesion not established\", \"Mammalian conservation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified CENP-A as a Sgo1 interactor in yeast, with the Sgo1 N-terminal coiled-coil sufficient for CENP-A binding and core-centromere association required for genome stability.\",\n      \"evidence\": \"In vivo/in vitro Co-IP, domain deletion, ChIP, and chromosome loss assays in S. cerevisiae\",\n      \"pmids\": [\"28980861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CENP-A binding is direct vs bridged not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SET as a direct negative regulator that disrupts the SGO1-cohesin interaction to enable timely segregation, identifying an antagonist of cohesion protection.\",\n      \"evidence\": \"In vitro binding, mutagenesis, overexpression/depletion, and live-cell imaging in human cells\",\n      \"pmids\": [\"31227592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SET activity is regulated during the cell cycle not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed SGO1 binds the Borealin dimerization domain directly and simultaneously with PP2A, and that this interaction drives CPC chromosomal recruitment and Aurora B-dependent spindle assembly but not SAC signaling.\",\n      \"evidence\": \"Xenopus egg extract reconstitution, direct binding, and mutagenesis\",\n      \"pmids\": [\"32697622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between Borealin and Survivin contacts not fully integrated here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the histone-H3-like SGO1 N-terminal tail-Survivin BIR domain interaction as the essential hotspot for CPC-SGO1 assembly, with SGO1 and H3T3ph competing for the same Survivin surface.\",\n      \"evidence\": \"Integrative structure-function analysis, mutagenesis, and Co-IP in human cells\",\n      \"pmids\": [\"35776132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How competition with H3T3ph is regulated in time/space not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established in human cells that basic C-terminal SGO1 residues mediate CENP-A binding and that this interaction determines SGO1 and Aurora B centromere localization and segregation fidelity.\",\n      \"evidence\": \"Co-IP, site-directed charge-reversal mutagenesis, and segregation assays in human cells\",\n      \"pmids\": [\"37777834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CENP-A binding is direct not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular signal that couples kinetochore tension to SGO1 dephosphorylation and redistribution, and the mechanism by which the CAID-causing K23E substitution disrupts SGO1 function, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of tension-driven SGO1 conformational/positional change\", \"No mechanistic explanation of K23E pathogenicity\", \"Identity of the SGO1-associated RNA enabling cohesin access undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 16, 18, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 11, 24]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 10, 11, 21]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\n      \"chromosomal passenger complex (CPC)\",\n      \"cohesin\",\n      \"SGO1-PP2A\"\n    ],\n    \"partners\": [\n      \"PP2A\",\n      \"Bub1\",\n      \"Survivin\",\n      \"Borealin\",\n      \"CENP-A\",\n      \"NEK2A\",\n      \"SET\",\n      \"Plk1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}