{"gene":"SCMH1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1999,"finding":"SCMH1 (Sex comb on midleg homolog 1) was cloned as a mammalian homolog of Drosophila Scm. The protein contains two MBT (malignant brain tumor) repeats and an SPM domain characteristic of Scm, but lacks the cysteine clusters and serine/threonine-rich N-terminal region found in Drosophila Scm. Mouse Scmh1 interacts in vitro with the mammalian polyhomeotic homolog RAE28/mph1 via their SPM domains. Human SCMH1 shows 94% identity to mouse Scmh1 and 41% identity to Drosophila Scm, and maps to chromosome 1p34.","method":"cDNA library screening, in vitro SPM domain interaction assay, northern blotting, in situ hybridization, chromosomal mapping","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro interaction validated by domain mutagenesis logic; single lab, two orthogonal methods (pulldown + expression analysis)","pmids":["10653359","10524249"],"is_preprint":false},{"year":2002,"finding":"SCMH1 (SCM homolog) is a constituent of the purified human Polycomb repressive complex 1 (hPRC-H) isolated from HeLa cells. The complex retains the PcG core proteins but has fewer components than Drosophila PRC1. hPRC-H can block remodeling of nucleosomal arrays, demonstrating functional conservation of the complex containing SCMH1.","method":"Affinity purification of hPRC-H from HeLa cells, mass spectrometry identification of components, nucleosomal remodeling assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical purification with functional assay; single lab, two orthogonal methods","pmids":["12167701"],"is_preprint":false},{"year":2004,"finding":"Geminin, a cell-cycle regulator, associates transiently with members of the Hox-repressing polycomb complex. The interaction domain for geminin within PRC1 is provided by Scmh1, establishing Scmh1 as the bridge between the polycomb complex and geminin.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), gain- and loss-of-function experiments in chick neural tube","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with functional in vivo epistasis; single lab but multiple orthogonal methods","pmids":["14973489"],"is_preprint":false},{"year":2007,"finding":"Scmh1 is an indispensable component of mammalian PRC1 and mediates exclusion of PRC1 (including Phc1, Phc2, Rnf110/Pcgf2, Bmi1, Cbx2) from the XY body at late pachytene in spermatocytes. Loss of Scmh1 causes apoptotic elimination of late pachytene spermatocytes accompanied by failure of specific chromatin modifications at the XY body. Restoration of Scmh1-deficient defects by Phc2 mutation demonstrates that Scmh1 exerts its molecular function via interaction with PRC1.","method":"Scmh1 knockout mice, immunostaining, genetic epistasis (Scmh1-/-; Phc2 double mutant), chromatin modification analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype plus genetic epistasis with double mutant rescue; multiple orthogonal methods","pmids":["17215307"],"is_preprint":false},{"year":2008,"finding":"Scmh1 mediates recruitment of the geminin interaction domain into PRC1 (via Rae28/mph1). PRC1 acts as an E3 ubiquitin ligase for geminin both in vivo and in vitro using purified recombinant PRC1 reconstituted in insect cells, regulating geminin protein stability and hematopoietic stem cell activity. Deficiency of Rae28 (which recruits Scmh1) impairs ubiquitin-proteasome-mediated degradation of geminin, causing geminin accumulation and elimination of hematopoietic stem cell activity.","method":"Rae28-deficient mice, in vitro E3 ubiquitin ligase reconstitution assay with purified recombinant PRC1 from insect cells, retroviral transduction experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of E3 ligase activity with purified recombinant complex, validated in vivo with KO mice","pmids":["18650381"],"is_preprint":false},{"year":2012,"finding":"Scmh1 itself has E3 ubiquitin ligase activity for both geminin and histone H2A. Loss of Scmh1 in mice causes derepression of Hoxb4 and Hoxa9 (direct PRC1 targets in hematopoietic cells). The derepressed Hoxb4 and Hoxa9 proteins each form a complex with Roc1-Ddb1-Cul4a to act as E3 ubiquitin ligases for geminin, providing a compensatory mechanism. A Scmh1 mutant lacking the geminin-binding domain restores Hoxb4/Hoxa9 repression but fails to downregulate geminin, demonstrating that the geminin-binding domain of Scmh1 is required for direct geminin regulation independent of Hox-mediated repression.","method":"Scmh1-deficient mice, double knockdown of Hoxb4 and Hoxa9, dominant-negative Hoxb4N→A transduction, retroviral domain-deletion mutant rescue, in vitro ubiquitin ligase assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro E3 ligase assay, domain-deletion mutagenesis, genetic epistasis with double knockdown; multiple orthogonal methods in single rigorous study","pmids":["23207902"],"is_preprint":false},{"year":2012,"finding":"Comprehensive proteomic analysis of PRC1 complexes established that CBX/PHC/SCM (including SCMH1) define one class of PRC1 complexes, while RYBP/YAF2 defines a mutually exclusive class. The two classes differ in H2AK119ub1 activity, with RYBP stimulating RING1B ubiquitin ligase activity more potently. Only a small subset of PRC1 complexes co-localize with H3K27me3, indicating that SCMH1-containing canonical PRC1 and RYBP-containing non-canonical PRC1 have distinct genomic distributions.","method":"Affinity purification-mass spectrometry, ChIP-seq, knockdown in embryonic stem cells","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative proteomics plus ChIP-seq; large-scale study but SCM subunit resolution is part of broader analysis","pmids":["22325352"],"is_preprint":false}],"current_model":"SCMH1 is a substoichiometric component of mammalian Polycomb repressive complex 1 (PRC1) that harbors E3 ubiquitin ligase activity toward both histone H2A and geminin; it provides PRC1 with a geminin-interaction domain (recruited via RAE28/mph1 through SPM domain interaction), mediates exclusion of PRC1 from the XY body in pachytene spermatocytes, represses Hox gene targets (Hoxb4, Hoxa9) in hematopoietic cells, and regulates geminin stability both directly (via its own E3 activity) and indirectly (through transcriptional silencing of Hox genes that themselves ubiquitinate geminin via Roc1-Ddb1-Cul4a complexes)."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of SCMH1 as the mammalian Scm ortholog established that PcG SPM-domain architecture is conserved and that SCMH1 physically contacts the polyhomeotic homolog RAE28/mph1, providing the first molecular handle on how SCM-class proteins integrate into mammalian PRC1.","evidence":"cDNA cloning, in vitro SPM-domain pulldown, northern blot expression profiling in mouse and human","pmids":["10653359","10524249"],"confidence":"Medium","gaps":["In vitro interaction only; endogenous complex membership not demonstrated","Functional consequence of SCMH1–RAE28 interaction unknown","No loss-of-function data"]},{"year":2002,"claim":"Biochemical purification of human PRC1 (hPRC-H) confirmed SCMH1 as a bona fide constituent of the endogenous complex, which retained nucleosomal remodeling-blocking activity, establishing functional conservation with Drosophila PRC1.","evidence":"Affinity purification from HeLa cells, mass spectrometry, nucleosome remodeling assay","pmids":["12167701"],"confidence":"Medium","gaps":["Stoichiometry of SCMH1 within hPRC-H not determined","Specific contribution of SCMH1 to remodeling-blocking activity not tested"]},{"year":2004,"claim":"Discovery that geminin associates with PRC1 through a domain provided by Scmh1 linked PRC1 function to cell-cycle control, revealing a previously unsuspected bridge between chromatin-based gene silencing and replication licensing.","evidence":"Co-immunoprecipitation, ChIP, gain- and loss-of-function in chick neural tube","pmids":["14973489"],"confidence":"Medium","gaps":["Direct versus indirect interaction not resolved at this stage","Functional consequence of geminin–Scmh1 interaction for PRC1 target genes not shown"]},{"year":2007,"claim":"Scmh1 knockout mice demonstrated an essential in vivo role for Scmh1 in spermatogenesis: Scmh1 mediates exclusion of PRC1 from the XY body at late pachytene, and genetic rescue by Phc2 mutation proved this function operates through PRC1.","evidence":"Scmh1−/− mice, Scmh1−/−;Phc2 double mutants, immunostaining, chromatin modification analysis","pmids":["17215307"],"confidence":"High","gaps":["Molecular mechanism of PRC1 exclusion from XY body not defined","Whether Scmh1 role in XY body depends on geminin interaction unknown"]},{"year":2008,"claim":"Reconstitution of PRC1 E3 ubiquitin ligase activity toward geminin in vitro, coupled with Rae28-deficient mice showing geminin accumulation and loss of hematopoietic stem cell activity, established that the Scmh1-containing arm of PRC1 controls geminin protein stability through ubiquitin-proteasome-mediated degradation.","evidence":"Purified recombinant PRC1 from insect cells, in vitro E3 ubiquitin ligase assay, Rae28−/− mice, retroviral transduction","pmids":["18650381"],"confidence":"High","gaps":["Whether Scmh1 itself or another PRC1 subunit provides the catalytic E3 activity not separated","Ubiquitin linkage type on geminin not characterized"]},{"year":2012,"claim":"Two advances resolved SCMH1's dual mechanism: (1) Scmh1 itself possesses E3 ligase activity for both H2A and geminin, with a separable geminin-binding domain required for direct geminin regulation independent of Hox-mediated repression; and (2) proteomic classification of PRC1 complexes placed SCMH1 in the CBX/PHC/SCM canonical class that is mutually exclusive with RYBP-containing non-canonical PRC1.","evidence":"In vitro ubiquitin ligase assays, domain-deletion rescue, Hoxb4/Hoxa9 double knockdown, AP-MS and ChIP-seq in ESCs","pmids":["23207902","22325352"],"confidence":"High","gaps":["Structural basis for SCMH1 E3 ligase activity not determined","Relative contribution of SCMH1 versus RING1B to H2A ubiquitination within the same complex unclear","Genome-wide target map specific to SCMH1-containing PRC1 not available"]},{"year":null,"claim":"The structural determinants of SCMH1's intrinsic E3 ligase activity, the genome-wide binding profile specific to SCMH1-containing canonical PRC1, and the potential role of MBT repeats in chromatin reading remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SCMH1 or its catalytic mechanism","MBT repeat ligand specificity not determined for mammalian SCMH1","Genome-wide ChIP-seq for SCMH1 itself not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,3,5,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":["PRC1 (canonical CBX/PHC/SCM class)"],"partners":["RAE28","PHC2","RING1B","BMI1","CBX2","GMNN"],"other_free_text":[]},"mechanistic_narrative":"SCMH1 is a mammalian Polycomb group protein that functions as a substoichiometric subunit of canonical Polycomb repressive complex 1 (PRC1), where it bridges PRC1 to the cell-cycle regulator geminin and contributes intrinsic E3 ubiquitin ligase activity toward both histone H2A and geminin [PMID:23207902, PMID:14973489]. SCMH1 integrates into PRC1 through SPM-domain–mediated interaction with RAE28/PHC proteins [PMID:10653359] and defines the CBX/PHC/SCM class of canonical PRC1 complexes that are mutually exclusive with RYBP-containing non-canonical PRC1 [PMID:22325352]. In spermatogenesis, Scmh1 is required for exclusion of PRC1 from the XY body at late pachytene, and its loss causes apoptotic elimination of pachytene spermatocytes, a phenotype rescued by Phc2 mutation, confirming that Scmh1 acts through PRC1 [PMID:17215307]. In hematopoietic cells, Scmh1 represses Hox targets (Hoxb4, Hoxa9) and independently regulates geminin stability via its geminin-binding domain, with derepressed Hox proteins providing a compensatory geminin-degradation pathway through Roc1-Ddb1-Cul4a complexes [PMID:23207902, PMID:18650381]."},"prefetch_data":{"uniprot":{"accession":"Q96GD3","full_name":"Polycomb protein SCMH1","aliases":["Sex comb on midleg homolog 1"],"length_aa":660,"mass_kda":73.4,"function":"Associates with Polycomb group (PcG) multiprotein complexes; the complex class is required to maintain the transcriptionally repressive state of some genes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96GD3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCMH1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SCMH1","total_profiled":1310},"omim":[{"mim_id":"616396","title":"SCM POLYCOMB GROUP PROTEIN HOMOLOG 1; SCMH1","url":"https://www.omim.org/entry/616396"},{"mim_id":"602978","title":"POLYHOMEOTIC HOMOLOG 1; PHC1","url":"https://www.omim.org/entry/602978"},{"mim_id":"602842","title":"GEMININ DNA REPLICATION INHIBITOR; GMNN","url":"https://www.omim.org/entry/602842"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCMH1"},"hgnc":{"alias_symbol":["Scml3"],"prev_symbol":[]},"alphafold":{"accession":"Q96GD3","domains":[{"cath_id":"2.30.30.140","chopping":"29-49_159-227","consensus_level":"high","plddt":96.4826,"start":29,"end":227},{"cath_id":"2.30.30.140","chopping":"61-153","consensus_level":"high","plddt":95.5755,"start":61,"end":153},{"cath_id":"3.90.1150.190","chopping":"357-463","consensus_level":"high","plddt":91.628,"start":357,"end":463},{"cath_id":"1.10.150.50","chopping":"589-656","consensus_level":"high","plddt":91.0168,"start":589,"end":656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GD3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GD3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GD3-F1-predicted_aligned_error_v6.png","plddt_mean":70.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCMH1","jax_strain_url":"https://www.jax.org/strain/search?query=SCMH1"},"sequence":{"accession":"Q96GD3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GD3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GD3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GD3"}},"corpus_meta":[{"pmid":"32441115","id":"PMC_32441115","title":"Extracellular 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TRRAP-TIP60 complex and promotes tumorigenesis.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35906200","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7509,"output_tokens":2480,"usd":0.029864},"stage2":{"model":"claude-opus-4-6","input_tokens":5779,"output_tokens":2841,"usd":0.14988},"total_usd":0.36052,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":19783,"output_tokens":3294,"usd":0.054379},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5793,"output_tokens":2212,"usd":0.126397}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SCMH1 (human homolog of Drosophila Sex comb on midleg) contains two MBT domains and an SPM domain characteristic of Scm, and is widely expressed in adult human tissues; it maps to chromosome 1p34.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain architecture established by direct cloning and sequence analysis; single lab, single method\",\n      \"pmids\": [\"10524249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SCMH1 (Scmh1) is a constituent of mammalian Polycomb Repressive Complex 1 (PRC1) and is excluded from the XY body in late pachytene spermatocytes together with other PRC1 components (Phc1, Phc2, Rnf110/Pcgf2, Bmi1, Cbx2); loss of Scmh1 causes apoptotic elimination of late pachytene spermatocytes accompanied by failure of specific chromatin modifications at the XY body, and Phc2 mutation rescues Scmh1-deficient spermatocytes, placing Scmh1 upstream of Phc2 within PRC1.\",\n      \"method\": \"Scmh1 knockout mice, immunostaining, genetic epistasis (Scmh1/Phc2 double mutant), chromatin modification analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined phenotype + genetic epistasis rescue, replicated across multiple PRC1 components\",\n      \"pmids\": [\"17215307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Scmh1 acts as an E3 ubiquitin ligase for both histone H2A and geminin as part of PRC1; Scmh1 provides PRC1 with an interaction domain for geminin; loss of Scmh1 causes derepression of Hoxb4 and Hoxa9 in hematopoietic cells; derepressed Hoxb4 and Hoxa9 each form a complex with Roc1-Ddb1-Cul4a to act as an E3 ubiquitin ligase for geminin, composing a homeostatic regulatory loop; Scmh1 lacking the geminin-binding domain restores Hoxb4/Hoxa9 repression but cannot downregulate geminin, demonstrating distinct functional domains.\",\n      \"method\": \"Scmh1-deficient mice, in vitro ubiquitin ligase assay, double knockdown, dominant-negative mutant transduction, domain-deletion rescue experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro E3 ligase assay plus domain mutagenesis rescue plus KO phenotype in a single study\",\n      \"pmids\": [\"23207902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Circular RNA SCMH1 (circSCMH1), derived from the SCMH1 locus, mechanistically binds to the transcription factor MeCP2, thereby releasing repression of MeCP2 target gene transcription; this promotes neuronal plasticity and inhibits glial activation after ischemic stroke.\",\n      \"method\": \"Proteomic assays, RNA-sequencing/transcriptional profiling, RBP pulldown (circSCMH1–MeCP2 interaction), extracellular vesicle delivery in rodent and nonhuman primate stroke models\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction validated by pulldown/proteomic assay with functional in vivo phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32441115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CircSCMH1 (circ-SCMH1/hsa_circ_0011946) directly sponges miR-338-3p to upregulate LIN28B, promoting cisplatin resistance in oral squamous cell carcinoma cells; circ-SCMH1 is packaged as cargo in extracellular vesicles released by drug-resistant OSCC cells and can transfer resistance to parental cells.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA immunoprecipitation, RNA pulldown, MTT/flow cytometry/transwell assays, xenograft experiment, EV characterization (TEM, nanoparticle tracking, western blot)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction validated by dual-luciferase + RIP + pulldown with functional rescue; single lab\",\n      \"pmids\": [\"34353342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircSCMH1 positively regulates ZEB1 expression by sponging miR-200a-3p, thereby promoting epithelial-mesenchymal transition in retinal pigment epithelial cells under high-glucose conditions relevant to diabetic retinopathy.\",\n      \"method\": \"RIP, dual-luciferase reporter assay, FISH localization of circSCMH1 and miR-200a-3p, western blot, circSCMH1 silencing in ARPE-19 cells and mouse DR model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by RIP and dual-luciferase with in vivo validation; single lab\",\n      \"pmids\": [\"36162459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CircSCMH1 (circ-Scmh1) promotes microglial M2 polarization after traumatic brain injury by sponging miR-154-5p, thereby relieving repression of STAT6; overexpression of miR-154-5p or inhibition of STAT6 reverses circ-Scmh1-induced M2 polarization.\",\n      \"method\": \"Luciferase reporter assay, next-generation sequencing, exosome delivery, TBI mouse model, cytokine/polarization assays\",\n      \"journal\": \"Injury\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by luciferase assay with functional epistasis rescue; single lab\",\n      \"pmids\": [\"37544863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CircSCMH1 inhibits KMO expression by binding to the transcription activator STAT5B, thereby impeding STAT5B nuclear translocation; this suppresses KMO-driven mitophagy and enhances mitochondrial fusion to promote post-stroke brain repair.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), RNA pulldown, immunofluorescence, western blot, metabolomics and transcriptomics in photothrombotic stroke mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by ChIP and pulldown with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"39659575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTBP1 binds specifically to the 800-882 segment at the 3′ end of circSCMH1's flanking intron, inhibiting back-splicing and reducing circSCMH1 production; PTBP1-mediated suppression of circSCMH1 biogenesis exacerbates post-stroke brain injury.\",\n      \"method\": \"RNA immunoprecipitation, computational RBP binding-site analysis, transcriptomic sequencing, functional assays in stroke model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP validates PTBP1–pre-circSCMH1 interaction with functional consequence; single lab, single study\",\n      \"pmids\": [\"41328340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCMH1 protein is a substoichiometric component of Polycomb Repressive Complex 1 (PRC1) that provides the complex with a geminin-interaction domain, possesses intrinsic E3 ubiquitin ligase activity toward histone H2A and geminin, represses Hoxb4 and Hoxa9 transcription in hematopoietic cells to regulate geminin stability, and mediates exclusion of PRC1 from the XY body in pachytene spermatocytes; its cognate circular RNA (circSCMH1) operates through distinct mechanisms including MeCP2 sequestration, STAT5B nuclear-translocation inhibition (suppressing KMO/mitophagy), and miRNA sponging (miR-338-3p/LIN28B, miR-200a-3p/ZEB1, miR-154-5p/STAT6), while circSCMH1 biogenesis itself is negatively regulated by PTBP1 binding to its flanking intron.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\n**Retrieved Papers:**\n1. PMID:32441115 — circSCMH1 (circular RNA) → EXCLUDE (case B: alt-locus product, circRNA not canonical protein)\n2. PMID:17215307 — Mammalian Scmh1 protein, PRC1 component → **KEEP**\n3. PMID:40143778 — circSCMH1 delivery → EXCLUDE (case B)\n4. PMID:34353342 — circ-SCMH1 → EXCLUDE (case B)\n5. PMID:10524249 — Human SCMH1 protein cloning → **KEEP**\n6. PMID:39659575 — circSCMH1 → EXCLUDE (case B)\n7. PMID:37544863 — circ-Scmh1 → EXCLUDE (case B)\n8. PMID:37664885 — hsa-SCMH1_0001 circRNA → EXCLUDE (case B)\n9. PMID:23207902 — Scmh1 E3 ubiquitin ligase → **KEEP**\n10. PMID:36162459 — CircRNA SCMH1 → EXCLUDE (case B)\n11. PMID:41328340 — circSCMH1 biogenesis → EXCLUDE (case B)\n\n**gene2pubmed Papers:**\n- PMID:17081983 — phosphoproteomics, SCMH1 incidental → EXCLUDE\n- PMID:16169070 — general interactome → EXCLUDE\n- PMID:12477932 — cDNA collection → EXCLUDE\n- PMID:20881960 — GWAS height → EXCLUDE\n- PMID:28514442 — BioPlex 2.0 general interactome → EXCLUDE\n- PMID:26496610 — general interactome → EXCLUDE\n- PMID:25416956 — general interactome → EXCLUDE\n- PMID:32296183 — general interactome → EXCLUDE\n- PMID:14702039 — cDNA sequencing → EXCLUDE\n- PMID:33961781 — BioPlex 3.0 general → EXCLUDE\n- PMID:22325352 — PRC1 complexes, mentions SCM proteins generally → **KEEP** (describes SCMH1/SCM in PRC1 context)\n- PMID:21873635 — GO annotation → EXCLUDE\n- PMID:18391952 — GWAS height → EXCLUDE\n- PMID:23563607 — GWAS → EXCLUDE\n- PMID:20211142 — TF interactions → EXCLUDE\n- PMID:19266077 — GWAS height → EXCLUDE\n- PMID:15489334 — MGC cDNA → EXCLUDE\n- PMID:12167701 — hPRC-H purification → **KEEP**\n- PMID:14973489 — geminin/polycomb → **KEEP**\n- PMID:21653829 — ASD interactome → EXCLUDE\n- PMID:16710414 — chromosome 1 sequence → EXCLUDE\n- PMID:30554943 — BET bromodomain → EXCLUDE\n- PMID:24457600 — EED/PRC → **KEEP** (mentions SCMH1 in PRC1 context)\n- PMID:18650381 — Rae28/Scmh1/Geminin E3 ligase → **KEEP**\n- PMID:36138187 — CD19/B-ALL → EXCLUDE\n- PMID:10653359 — Scmh1 mouse cloning, RAE28 interaction → **KEEP**\n- PMID:24981860 — chromatin interactome → EXCLUDE\n- PMID:20546612 — GWAS height → EXCLUDE\n- PMID:35906200 — HSF1/TIP60 → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SCMH1 (Sex comb on midleg homolog 1) was cloned as a mammalian homolog of Drosophila Scm. The protein contains two MBT (malignant brain tumor) repeats and an SPM domain characteristic of Scm, but lacks the cysteine clusters and serine/threonine-rich N-terminal region found in Drosophila Scm. Mouse Scmh1 interacts in vitro with the mammalian polyhomeotic homolog RAE28/mph1 via their SPM domains. Human SCMH1 shows 94% identity to mouse Scmh1 and 41% identity to Drosophila Scm, and maps to chromosome 1p34.\",\n      \"method\": \"cDNA library screening, in vitro SPM domain interaction assay, northern blotting, in situ hybridization, chromosomal mapping\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro interaction validated by domain mutagenesis logic; single lab, two orthogonal methods (pulldown + expression analysis)\",\n      \"pmids\": [\"10653359\", \"10524249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SCMH1 (SCM homolog) is a constituent of the purified human Polycomb repressive complex 1 (hPRC-H) isolated from HeLa cells. The complex retains the PcG core proteins but has fewer components than Drosophila PRC1. hPRC-H can block remodeling of nucleosomal arrays, demonstrating functional conservation of the complex containing SCMH1.\",\n      \"method\": \"Affinity purification of hPRC-H from HeLa cells, mass spectrometry identification of components, nucleosomal remodeling assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification with functional assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"12167701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Geminin, a cell-cycle regulator, associates transiently with members of the Hox-repressing polycomb complex. The interaction domain for geminin within PRC1 is provided by Scmh1, establishing Scmh1 as the bridge between the polycomb complex and geminin.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), gain- and loss-of-function experiments in chick neural tube\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with functional in vivo epistasis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"14973489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Scmh1 is an indispensable component of mammalian PRC1 and mediates exclusion of PRC1 (including Phc1, Phc2, Rnf110/Pcgf2, Bmi1, Cbx2) from the XY body at late pachytene in spermatocytes. Loss of Scmh1 causes apoptotic elimination of late pachytene spermatocytes accompanied by failure of specific chromatin modifications at the XY body. Restoration of Scmh1-deficient defects by Phc2 mutation demonstrates that Scmh1 exerts its molecular function via interaction with PRC1.\",\n      \"method\": \"Scmh1 knockout mice, immunostaining, genetic epistasis (Scmh1-/-; Phc2 double mutant), chromatin modification analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus genetic epistasis with double mutant rescue; multiple orthogonal methods\",\n      \"pmids\": [\"17215307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Scmh1 mediates recruitment of the geminin interaction domain into PRC1 (via Rae28/mph1). PRC1 acts as an E3 ubiquitin ligase for geminin both in vivo and in vitro using purified recombinant PRC1 reconstituted in insect cells, regulating geminin protein stability and hematopoietic stem cell activity. Deficiency of Rae28 (which recruits Scmh1) impairs ubiquitin-proteasome-mediated degradation of geminin, causing geminin accumulation and elimination of hematopoietic stem cell activity.\",\n      \"method\": \"Rae28-deficient mice, in vitro E3 ubiquitin ligase reconstitution assay with purified recombinant PRC1 from insect cells, retroviral transduction experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of E3 ligase activity with purified recombinant complex, validated in vivo with KO mice\",\n      \"pmids\": [\"18650381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Scmh1 itself has E3 ubiquitin ligase activity for both geminin and histone H2A. Loss of Scmh1 in mice causes derepression of Hoxb4 and Hoxa9 (direct PRC1 targets in hematopoietic cells). The derepressed Hoxb4 and Hoxa9 proteins each form a complex with Roc1-Ddb1-Cul4a to act as E3 ubiquitin ligases for geminin, providing a compensatory mechanism. A Scmh1 mutant lacking the geminin-binding domain restores Hoxb4/Hoxa9 repression but fails to downregulate geminin, demonstrating that the geminin-binding domain of Scmh1 is required for direct geminin regulation independent of Hox-mediated repression.\",\n      \"method\": \"Scmh1-deficient mice, double knockdown of Hoxb4 and Hoxa9, dominant-negative Hoxb4N→A transduction, retroviral domain-deletion mutant rescue, in vitro ubiquitin ligase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro E3 ligase assay, domain-deletion mutagenesis, genetic epistasis with double knockdown; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23207902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Comprehensive proteomic analysis of PRC1 complexes established that CBX/PHC/SCM (including SCMH1) define one class of PRC1 complexes, while RYBP/YAF2 defines a mutually exclusive class. The two classes differ in H2AK119ub1 activity, with RYBP stimulating RING1B ubiquitin ligase activity more potently. Only a small subset of PRC1 complexes co-localize with H3K27me3, indicating that SCMH1-containing canonical PRC1 and RYBP-containing non-canonical PRC1 have distinct genomic distributions.\",\n      \"method\": \"Affinity purification-mass spectrometry, ChIP-seq, knockdown in embryonic stem cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative proteomics plus ChIP-seq; large-scale study but SCM subunit resolution is part of broader analysis\",\n      \"pmids\": [\"22325352\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCMH1 is a substoichiometric component of mammalian Polycomb repressive complex 1 (PRC1) that harbors E3 ubiquitin ligase activity toward both histone H2A and geminin; it provides PRC1 with a geminin-interaction domain (recruited via RAE28/mph1 through SPM domain interaction), mediates exclusion of PRC1 from the XY body in pachytene spermatocytes, represses Hox gene targets (Hoxb4, Hoxa9) in hematopoietic cells, and regulates geminin stability both directly (via its own E3 activity) and indirectly (through transcriptional silencing of Hox genes that themselves ubiquitinate geminin via Roc1-Ddb1-Cul4a complexes).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SCMH1 is a Polycomb group protein and constituent of mammalian Polycomb Repressive Complex 1 (PRC1) that functions in transcriptional repression and ubiquitin-mediated protein regulation, while its cognate circular RNA (circSCMH1) operates through mechanistically distinct pathways involving transcription factor sequestration and miRNA sponging. The SCMH1 protein contains MBT and SPM domains, possesses intrinsic E3 ubiquitin ligase activity toward histone H2A and geminin, and represses Hoxb4 and Hoxa9 in hematopoietic cells; loss of Scmh1 derepresses these Hox genes, which then assemble Roc1-Ddb1-Cul4a E3 ligase complexes to degrade geminin, forming a homeostatic regulatory loop [PMID:23207902]. In spermatogenesis, Scmh1 mediates the exclusion of PRC1 from the XY body in pachytene spermatocytes, and its loss causes apoptotic elimination of late pachytene cells, a phenotype rescued by concurrent Phc2 mutation, establishing an epistatic hierarchy within PRC1 [PMID:17215307]. CircSCMH1 functions independently of the protein by sequestering MeCP2 to derepress neuronal plasticity genes, blocking STAT5B nuclear translocation to suppress KMO-driven mitophagy, and sponging miR-338-3p, miR-200a-3p, and miR-154-5p to regulate LIN28B, ZEB1, and STAT6 expression, respectively, with its biogenesis negatively regulated by PTBP1 binding to the flanking intron [PMID:32441115, PMID:39659575, PMID:34353342, PMID:41328340].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that mammals encode a Drosophila Scm ortholog resolved the question of whether Polycomb-group repression via MBT/SPM-domain proteins is conserved in vertebrates.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and chromosomal mapping of human SCMH1\",\n      \"pmids\": [\"10524249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional data; domain roles inferred solely from Drosophila homology\",\n        \"Expression data limited to RNA level without protein-level confirmation\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout studies revealed that Scmh1 is required for spermatocyte survival and XY-body chromatin remodeling, and that it acts upstream of Phc2 within PRC1, answering how individual PRC1 subunits contribute to mammalian meiosis.\",\n      \"evidence\": \"Scmh1-null mice, immunostaining of PRC1 at the XY body, genetic epistasis via Scmh1/Phc2 double mutant rescue\",\n      \"pmids\": [\"17215307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which Scmh1 controls Phc2 function or PRC1 exclusion from the XY body is not defined\",\n        \"Whether Scmh1 has catalytic activity was not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that Scmh1 is an E3 ubiquitin ligase for H2A and geminin, and that its loss triggers a Hoxb4/Hoxa9–Cul4a feedback loop degrading geminin, established Scmh1 as both a transcriptional repressor and a key node in geminin homeostasis.\",\n      \"evidence\": \"In vitro ubiquitin ligase assays, domain-deletion rescue, double knockdown, and Scmh1-deficient hematopoietic cell analysis\",\n      \"pmids\": [\"23207902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of H2A versus geminin substrate selectivity unknown\",\n        \"Whether the E3 activity is relevant in spermatocytes or other in vivo contexts besides hematopoiesis remains untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that circSCMH1 sequesters MeCP2 to derepress target genes after stroke revealed a protein-independent function of the SCMH1 locus, opening a distinct mechanistic axis for this gene.\",\n      \"evidence\": \"RNA pulldown, proteomic assays, transcriptional profiling, and extracellular vesicle delivery in rodent and primate stroke models\",\n      \"pmids\": [\"32441115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of circSCMH1–MeCP2 interaction unresolved\",\n        \"Whether circSCMH1 operates in normal (non-stroke) brain physiology not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of circSCMH1 as a miR-338-3p sponge that upregulates LIN28B established a miRNA-axis mechanism for this circular RNA, distinct from its MeCP2-sequestration function.\",\n      \"evidence\": \"Dual-luciferase, RIP, RNA pulldown, and xenograft assays in cisplatin-resistant oral squamous cell carcinoma cells\",\n      \"pmids\": [\"34353342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether miRNA sponging and MeCP2 sequestration co-occur in the same cell type is unknown\",\n        \"Functional relevance outside cancer cell lines not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that circSCMH1 sponges miR-200a-3p to upregulate ZEB1 and drive EMT in retinal pigment epithelium broadened the miRNA-sponge repertoire of circSCMH1 to a second axis.\",\n      \"evidence\": \"RIP, dual-luciferase, FISH, western blot in ARPE-19 cells and diabetic retinopathy mouse model\",\n      \"pmids\": [\"36162459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No quantitative assessment of circSCMH1 copy number relative to miR-200a-3p\",\n        \"Independent replication in a second cell system not available\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CircSCMH1 was shown to sponge miR-154-5p to relieve STAT6 repression and drive microglial M2 polarization, extending the functional range of circSCMH1 to neuroimmune regulation after TBI.\",\n      \"evidence\": \"Luciferase reporter, next-generation sequencing, exosome delivery, TBI mouse model with cytokine and polarization assays\",\n      \"pmids\": [\"37544863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether endogenous circSCMH1 levels are sufficient to function as a miR-154-5p sponge in vivo is unaddressed\",\n        \"Relationship to the MeCP2-sequestration mechanism in the same cell type unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that circSCMH1 binds STAT5B and prevents its nuclear translocation, thereby suppressing KMO transcription and mitophagy, revealed a second protein-sequestration mechanism distinct from MeCP2 binding.\",\n      \"evidence\": \"ChIP, RNA pulldown, immunofluorescence, metabolomics/transcriptomics in photothrombotic stroke mouse model\",\n      \"pmids\": [\"39659575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether circSCMH1 binds STAT5B and MeCP2 simultaneously or competitively is unknown\",\n        \"No structural or biophysical characterization of the circSCMH1–STAT5B interface\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of PTBP1 as a negative regulator of circSCMH1 biogenesis through binding to the flanking intron answered how circSCMH1 levels are controlled, linking RNA-binding protein regulation to the functional output of the SCMH1 locus.\",\n      \"evidence\": \"RIP, computational RBP binding-site analysis, transcriptomic sequencing, functional stroke model assays\",\n      \"pmids\": [\"41328340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which PTBP1 binding inhibits back-splicing not structurally resolved\",\n        \"Whether PTBP1 regulation of circSCMH1 occurs in tissues beyond brain is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model integrating the protein-coding (PRC1/E3 ligase) and non-coding (circSCMH1) functions of the SCMH1 locus remains absent; it is unknown whether circSCMH1 production competes with mRNA production and whether the two outputs are coordinated in any physiological context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has simultaneously measured SCMH1 protein and circSCMH1 levels to assess locus-level regulation\",\n        \"In vivo relevance of the protein's E3 ligase activity outside hematopoiesis is untested\",\n        \"No structural model of SCMH1 protein or circSCMH1 secondary structure exists\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"PRC1\"\n    ],\n    \"partners\": [\n      \"PHC2\",\n      \"BMI1\",\n      \"GMNN\",\n      \"MECP2\",\n      \"STAT5B\",\n      \"PTBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SCMH1 is a mammalian Polycomb group protein that functions as a substoichiometric subunit of canonical Polycomb repressive complex 1 (PRC1), where it bridges PRC1 to the cell-cycle regulator geminin and contributes intrinsic E3 ubiquitin ligase activity toward both histone H2A and geminin [PMID:23207902, PMID:14973489]. SCMH1 integrates into PRC1 through SPM-domain–mediated interaction with RAE28/PHC proteins [PMID:10653359] and defines the CBX/PHC/SCM class of canonical PRC1 complexes that are mutually exclusive with RYBP-containing non-canonical PRC1 [PMID:22325352]. In spermatogenesis, Scmh1 is required for exclusion of PRC1 from the XY body at late pachytene, and its loss causes apoptotic elimination of pachytene spermatocytes, a phenotype rescued by Phc2 mutation, confirming that Scmh1 acts through PRC1 [PMID:17215307]. In hematopoietic cells, Scmh1 represses Hox targets (Hoxb4, Hoxa9) and independently regulates geminin stability via its geminin-binding domain, with derepressed Hox proteins providing a compensatory geminin-degradation pathway through Roc1-Ddb1-Cul4a complexes [PMID:23207902, PMID:18650381].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of SCMH1 as the mammalian Scm ortholog established that PcG SPM-domain architecture is conserved and that SCMH1 physically contacts the polyhomeotic homolog RAE28/mph1, providing the first molecular handle on how SCM-class proteins integrate into mammalian PRC1.\",\n      \"evidence\": \"cDNA cloning, in vitro SPM-domain pulldown, northern blot expression profiling in mouse and human\",\n      \"pmids\": [\"10653359\", \"10524249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro interaction only; endogenous complex membership not demonstrated\",\n        \"Functional consequence of SCMH1–RAE28 interaction unknown\",\n        \"No loss-of-function data\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Biochemical purification of human PRC1 (hPRC-H) confirmed SCMH1 as a bona fide constituent of the endogenous complex, which retained nucleosomal remodeling-blocking activity, establishing functional conservation with Drosophila PRC1.\",\n      \"evidence\": \"Affinity purification from HeLa cells, mass spectrometry, nucleosome remodeling assay\",\n      \"pmids\": [\"12167701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry of SCMH1 within hPRC-H not determined\",\n        \"Specific contribution of SCMH1 to remodeling-blocking activity not tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that geminin associates with PRC1 through a domain provided by Scmh1 linked PRC1 function to cell-cycle control, revealing a previously unsuspected bridge between chromatin-based gene silencing and replication licensing.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, gain- and loss-of-function in chick neural tube\",\n      \"pmids\": [\"14973489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect interaction not resolved at this stage\",\n        \"Functional consequence of geminin–Scmh1 interaction for PRC1 target genes not shown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Scmh1 knockout mice demonstrated an essential in vivo role for Scmh1 in spermatogenesis: Scmh1 mediates exclusion of PRC1 from the XY body at late pachytene, and genetic rescue by Phc2 mutation proved this function operates through PRC1.\",\n      \"evidence\": \"Scmh1−/− mice, Scmh1−/−;Phc2 double mutants, immunostaining, chromatin modification analysis\",\n      \"pmids\": [\"17215307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of PRC1 exclusion from XY body not defined\",\n        \"Whether Scmh1 role in XY body depends on geminin interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstitution of PRC1 E3 ubiquitin ligase activity toward geminin in vitro, coupled with Rae28-deficient mice showing geminin accumulation and loss of hematopoietic stem cell activity, established that the Scmh1-containing arm of PRC1 controls geminin protein stability through ubiquitin-proteasome-mediated degradation.\",\n      \"evidence\": \"Purified recombinant PRC1 from insect cells, in vitro E3 ubiquitin ligase assay, Rae28−/− mice, retroviral transduction\",\n      \"pmids\": [\"18650381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Scmh1 itself or another PRC1 subunit provides the catalytic E3 activity not separated\",\n        \"Ubiquitin linkage type on geminin not characterized\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two advances resolved SCMH1's dual mechanism: (1) Scmh1 itself possesses E3 ligase activity for both H2A and geminin, with a separable geminin-binding domain required for direct geminin regulation independent of Hox-mediated repression; and (2) proteomic classification of PRC1 complexes placed SCMH1 in the CBX/PHC/SCM canonical class that is mutually exclusive with RYBP-containing non-canonical PRC1.\",\n      \"evidence\": \"In vitro ubiquitin ligase assays, domain-deletion rescue, Hoxb4/Hoxa9 double knockdown, AP-MS and ChIP-seq in ESCs\",\n      \"pmids\": [\"23207902\", \"22325352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for SCMH1 E3 ligase activity not determined\",\n        \"Relative contribution of SCMH1 versus RING1B to H2A ubiquitination within the same complex unclear\",\n        \"Genome-wide target map specific to SCMH1-containing PRC1 not available\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural determinants of SCMH1's intrinsic E3 ligase activity, the genome-wide binding profile specific to SCMH1-containing canonical PRC1, and the potential role of MBT repeats in chromatin reading remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of SCMH1 or its catalytic mechanism\",\n        \"MBT repeat ligand specificity not determined for mammalian SCMH1\",\n        \"Genome-wide ChIP-seq for SCMH1 itself not reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"PRC1 (canonical CBX/PHC/SCM class)\"\n    ],\n    \"partners\": [\n      \"RAE28\",\n      \"PHC2\",\n      \"RING1B\",\n      \"BMI1\",\n      \"CBX2\",\n      \"GMNN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}