{"gene":"BRMS1L","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2004,"finding":"BRMS1L (referred to as 'p40') was identified as a novel component of the mSin3A/p33(ING1b)/HDAC1 histone deacetylase co-repressor complex by biochemical purification and mass spectrometry. The p40-associated complex showed strong HDAC activity, and when tethered to a Gal4 DNA-binding domain, Gal-p40 significantly repressed transcription of a Gal-luciferase reporter. BRMS1L bears homology to yeast Sds3 and mammalian mSds3, and overexpression inhibited cell growth.","method":"Biochemical purification, mass spectrometry, HDAC activity assay, Gal4-tethered transcriptional repression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical purification + MS + functional reporter assay, single study","pmids":["15451426"],"is_preprint":false},{"year":2014,"finding":"BRMS1L is a component of the Sin3A-HDAC co-repressor complex that suppresses breast cancer metastasis by epigenetically silencing FZD10 (a Wnt receptor) through HDAC1 recruitment and histone H3K9 deacetylation at the FZD10 promoter. This silencing inhibits aberrant WNT3-FZD10-β-catenin signalling and epithelial-mesenchymal transition. BRMS1L was also identified as a direct target of miR-106b, whose upregulation reduces BRMS1L levels in breast cancer cells.","method":"Co-immunoprecipitation, ChIP assay (H3K9 acetylation), luciferase reporter assay, siRNA knockdown, xenograft mouse model, miRNA target validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, luciferase, in vivo), single rigorous study with strong mechanistic support","pmids":["25406648"],"is_preprint":false},{"year":2017,"finding":"BRMS1L is a transcriptional target of p53 family proteins (p53, TAp63γ, TAp73β). Two p53 family response elements were identified in the first intron and upstream region of BRMS1L, conserved among mammals. Ectopic expression of BRMS1L inhibited cancer cell invasion and migration, while siRNA knockdown of BRMS1L induced the opposite effect, placing BRMS1L downstream of the p53 pathway in regulating cell invasion.","method":"Microarray analysis, luciferase reporter assay with response element mutations, siRNA knockdown, invasion/migration assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assays identifying response elements plus loss-of-function phenotype, single study","pmids":["29030916"],"is_preprint":false},{"year":2018,"finding":"miR-93-5p promotes lacrimal gland adenoid cystic carcinoma (LACC) cell migration, invasion, and proliferation by directly targeting and suppressing BRMS1L expression. Luciferase reporter assays confirmed miR-93-5p binding to the BRMS1L 3'-UTR. BRMS1L overexpression inhibited EMT markers and suppressed Wnt signaling (reduced TOP/FOP luciferase activity), while miR-93-5p overexpression activated Wnt signaling in a BRMS1L-dependent manner.","method":"Luciferase reporter assay (3'-UTR targeting), western blotting, qRT-PCR, wound healing/transwell assays, TOP/FOP Wnt reporter assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — validated miRNA-target relationship with functional rescue experiments, single study","pmids":["29760585"],"is_preprint":false},{"year":2019,"finding":"miR-934 promotes ovarian cancer cell proliferation and inhibits apoptosis by targeting BRMS1L. Luciferase reporter assays confirmed direct miR-934 binding to BRMS1L mRNA. miR-934 inhibition increased BRMS1L expression, reduced Ki67 and Cyclin D1, and induced Caspase-3 activation, demonstrating BRMS1L's role in regulating the apoptosis/proliferation balance downstream of miR-934.","method":"Luciferase reporter assay, CCK-8 proliferation assay, TUNEL apoptosis assay, western blotting, qRT-PCR","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — validated miRNA-target binding with functional cellular phenotype, single study","pmids":["31298311"],"is_preprint":false}],"current_model":"BRMS1L is a component of the Sin3A-HDAC co-repressor complex that suppresses cancer metastasis primarily through epigenetic silencing of pro-metastatic target genes (including FZD10) via HDAC1 recruitment and histone H3K9 deacetylation, thereby inhibiting Wnt/β-catenin signalling and EMT; its expression is regulated downstream of p53 family transcription factors and is post-transcriptionally repressed by multiple miRNAs including miR-106b, miR-93-5p, and miR-934."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of BRMS1L as a stoichiometric component of the mSin3A/HDAC1 co-repressor complex established its molecular context as an HDAC-associated transcriptional co-repressor rather than a stand-alone DNA-binding factor.","evidence":"Biochemical purification and mass spectrometry of endogenous mSin3A complexes, Gal4-tethered repression reporter assay, HeLa cells","pmids":["15451426"],"confidence":"Medium","gaps":["Single study without reciprocal pull-down from BRMS1L bait","Direct chromatin targets of BRMS1L-containing complexes not identified","Whether BRMS1L is required for complex integrity or is an accessory subunit is unclear"]},{"year":2014,"claim":"Connecting BRMS1L's co-repressor activity to a specific metastasis-relevant pathway resolved how it suppresses breast cancer metastasis: BRMS1L recruits HDAC1 to the FZD10 promoter, deacetylates H3K9, silences FZD10, and thereby blocks Wnt/β-catenin-driven EMT.","evidence":"Co-immunoprecipitation, ChIP for H3K9ac at FZD10 promoter, siRNA knockdown, luciferase reporters, xenograft metastasis model in mice, miR-106b target validation, breast cancer cell lines","pmids":["25406648"],"confidence":"High","gaps":["Genome-wide binding profile of BRMS1L is unknown; FZD10 may not be the sole critical target","Whether BRMS1L loss is sufficient for metastasis in immunocompetent models is untested","Structural basis for BRMS1L–HDAC1 interaction not determined"]},{"year":2017,"claim":"Demonstrating that BRMS1L is a direct transcriptional target of p53, TAp63γ, and TAp73β placed it within the p53 tumour-suppressor axis, explaining how upstream tumour-suppressive signals converge on BRMS1L-mediated metastasis inhibition.","evidence":"Microarray screen, luciferase reporter assays with response-element mutations in BRMS1L intron 1 and upstream region, siRNA knockdown invasion/migration assays, cancer cell lines","pmids":["29030916"],"confidence":"Medium","gaps":["ChIP confirmation of endogenous p53-family occupancy at BRMS1L locus not shown","Relative contribution of each p53 family member under physiological conditions is unclear","Whether p53-dependent regulation is context-specific (e.g. tissue-type) is not addressed"]},{"year":2018,"claim":"Validation of miR-93-5p as a second miRNA repressor of BRMS1L in adenoid cystic carcinoma extended the miRNA-BRMS1L-Wnt axis beyond breast cancer, reinforcing BRMS1L as a general gatekeeper of Wnt/β-catenin activation across tumour types.","evidence":"3′-UTR luciferase reporter, TOP/FOP Wnt reporter, rescue by BRMS1L re-expression, LACC cell lines","pmids":["29760585"],"confidence":"Medium","gaps":["Single cancer type without in vivo validation","Whether miR-93-5p operates through BRMS1L in normal lacrimal tissue is unknown","Downstream Wnt target gene specificity not resolved"]},{"year":2019,"claim":"Identification of miR-934 as a third miRNA targeting BRMS1L in ovarian cancer linked BRMS1L loss to both increased proliferation and reduced apoptosis, broadening its tumour-suppressive functions beyond EMT/metastasis.","evidence":"3′-UTR luciferase reporter, CCK-8 proliferation, TUNEL apoptosis assay, western blot for Ki67/CyclinD1/Caspase-3, ovarian cancer cell lines","pmids":["31298311"],"confidence":"Medium","gaps":["Single study in one journal without in vivo confirmation","Mechanism by which BRMS1L regulates apoptosis (direct target genes) is not delineated","Specificity of miR-934 effect — other targets may contribute to the phenotype"]},{"year":null,"claim":"The genome-wide repertoire of BRMS1L-regulated loci, the structural basis of its integration into the Sin3A–HDAC complex, and its physiological role in non-cancer contexts remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide ChIP-seq or CUT&Tag profiling of BRMS1L","No structural or cryo-EM data for BRMS1L within the Sin3A complex","No genetic mouse model (knockout or conditional) characterising BRMS1L loss in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":["Sin3A-HDAC co-repressor complex"],"partners":["SIN3A","HDAC1","ING1"],"other_free_text":[]},"mechanistic_narrative":"BRMS1L is a subunit of the Sin3A–HDAC co-repressor complex that functions as a metastasis suppressor by mediating epigenetic silencing of pro-metastatic target genes [PMID:15451426, PMID:25406648]. It recruits HDAC1 to the FZD10 promoter, driving histone H3K9 deacetylation that silences FZD10 transcription and thereby inhibits WNT3–β-catenin signalling and epithelial-mesenchymal transition in breast cancer cells [PMID:25406648]. BRMS1L expression is transcriptionally activated by p53 family members (p53, TAp63γ, TAp73β) through conserved intronic and upstream response elements, and is post-transcriptionally repressed by miR-106b, miR-93-5p, and miR-934, linking its anti-metastatic activity to both tumour-suppressor and miRNA regulatory networks [PMID:29030916, PMID:25406648, PMID:29760585, PMID:31298311]."},"prefetch_data":{"uniprot":{"accession":"Q5PSV4","full_name":"Breast cancer metastasis-suppressor 1-like protein","aliases":["BRMS1-homolog protein p40","BRMS1-like protein p40"],"length_aa":323,"mass_kda":37.6,"function":"Involved in the histone deacetylase (HDAC1)-dependent transcriptional repression activity. When overexpressed in lung cancer cell line that lacks p53/TP53 expression, inhibits cell growth","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5PSV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BRMS1L","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BRMS1L","total_profiled":1310},"omim":[{"mim_id":"618514","title":"BRMS1-LIKE TRANSCRIPTIONAL REPRESSOR; BRMS1L","url":"https://www.omim.org/entry/618514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BRMS1L"},"hgnc":{"alias_symbol":["MGC11296","FLJ39177","p40"],"prev_symbol":["BRMS1"]},"alphafold":{"accession":"Q5PSV4","domains":[{"cath_id":"2.30.30","chopping":"253-321","consensus_level":"high","plddt":89.7946,"start":253,"end":321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5PSV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5PSV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5PSV4-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BRMS1L","jax_strain_url":"https://www.jax.org/strain/search?query=BRMS1L"},"sequence":{"accession":"Q5PSV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5PSV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5PSV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5PSV4"}},"corpus_meta":[{"pmid":"14707118","id":"PMC_14707118","title":"Increased 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/24981860","citation_count":80,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32814053","id":"PMC_32814053","title":"Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32814053","citation_count":79,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27634302","id":"PMC_27634302","title":"Dynamic Protein Interactions of the Polycomb Repressive Complex 2 during Differentiation of Pluripotent Cells.","date":"2016","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/27634302","citation_count":64,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29844126","id":"PMC_29844126","title":"The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29844126","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31515488","id":"PMC_31515488","title":"Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31515488","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37071682","id":"PMC_37071682","title":"Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37071682","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22984288","id":"PMC_22984288","title":"Human family with sequence similarity 60 member A (FAM60A) protein: a new subunit of the Sin3 deacetylase complex.","date":"2012","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/22984288","citation_count":47,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51006,"output_tokens":4095,"usd":0.107221},"stage2":{"model":"claude-opus-4-6","input_tokens":7587,"output_tokens":3625,"usd":0.19284},"total_usd":0.595005,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62809,"output_tokens":2157,"usd":0.110391},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5012,"output_tokens":3919,"usd":0.184553}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"BRMS1L is a component of the Sin3A-histone deacetylase (HDAC) co-repressor complex and suppresses breast cancer cell migration and invasion by epigenetically silencing FZD10 through HDAC1 recruitment and histone H3K9 deacetylation at the FZD10 promoter, thereby inhibiting WNT3-FZD10-β-catenin signaling. BRMS1L is also a direct target of miR-106b.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase reporter assay, RNAi knockdown, xenograft mouse model, rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, in vivo model) in a single rigorous study\",\n      \"pmids\": [\"25406648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRMS1L (identified as p40) is a novel component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex; when tethered to a Gal4 DNA-binding domain, Gal-p40 significantly represses transcription of a Gal-luciferase reporter, and overexpression of p40 in human cells inhibits cell growth.\",\n      \"method\": \"Biochemical purification, mass spectrometry, Gal4-tethering transcriptional repression assay, cell growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical purification with MS identification, functional transcription assay, and growth phenotype\",\n      \"pmids\": [\"15451426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRMS1L is a target gene of p53 family members (p53, TAp63γ, TAp73β); two p53-family response elements were identified in the first intron and upstream of BRMS1L, and ectopic expression of BRMS1L inhibited cancer cell invasion and migration while siRNA knockdown promoted the opposite.\",\n      \"method\": \"Microarray analysis, luciferase reporter assay with response element identification, ectopic expression and siRNA knockdown with invasion/migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with defined response elements plus functional loss/gain-of-function in a single study\",\n      \"pmids\": [\"29030916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRMS1 (closely related to BRMS1L) is posttranslationally regulated by TNF-induced CK2α' phosphorylation at serine 30, which promotes 14-3-3ε-mediated nuclear export, cytosolic accumulation, and ubiquitin-proteasome-dependent degradation of BRMS1; mutation of S30 abrogates CK2α'-induced cell migration/invasion and decreases metastasis ~60-fold in vivo.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, orthotopic mouse metastasis model, small-molecule CK2 inhibitor (CX4945), human NSCLC tissue analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus in vivo model plus clinical correlation, multiple orthogonal methods\",\n      \"pmids\": [\"26980766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A germline SNP (rs1052566, A273V) in BRMS1v2 abolishes its metastasis suppressor function by preventing interaction with nuclear Src, thereby activating c-fos-mediated transcription, upregulating CEACAM6, and driving metastasis in lung adenocarcinoma.\",\n      \"method\": \"Next-generation sequencing, co-immunoprecipitation, in vitro invasion assays, tail-vein xenograft and patient-derived organoid intracardiac injection metastasis models, c-fos inhibitor (T5224) treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic SNP characterization with mutagenesis, protein interaction studies, and multiple in vivo models\",\n      \"pmids\": [\"36197962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRMS1 is an integral component of the LSD1/CoREST corepressor complex; BRMS1 together with LSD1 are required for transcriptional suppression of metastasis-related target genes (including VIM, INSIG2, KLK11) and for inhibition of breast cancer cell migration and invasion.\",\n      \"method\": \"Affinity purification, mass spectrometry, RNA-seq, co-immunoprecipitation, migration/invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity purification/MS plus RNA-seq plus functional assays in a single study\",\n      \"pmids\": [\"30416854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM7 ubiquitinates BRMS1, promoting its degradation; TRIM7-mediated ubiquitination of BRMS1 regulates osteosarcoma cell migration, invasion, and chemoresistance.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, pulldown assay, ubiquitination assay, immunofluorescence, RNA immunoprecipitation for m6A modification\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with Co-IP/MS confirmation and functional cellular readout\",\n      \"pmids\": [\"32853985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRMS1 is ubiquitinated and destabilized by the Cul3-SPOP E3 ubiquitin ligase complex; SPOP serves as the adaptor protein mediating interaction between BRMS1 and Cul3, and SPOP knockdown increases BRMS1 protein levels and represses BRMS1 target genes OPN and uPA.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, protein stability assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with Co-IP and knockdown functional readout\",\n      \"pmids\": [\"22085717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRMS1 is stabilized by Hsp90; its turnover is proteasome-dependent. BRMS1 interacts with class II HDACs (HDAC4, 5, 6) and chaperones (DNAJB6/MRJ, Hsp90, Hsp70) in addition to known mSin3 complex components RBBP1 and mSDS3.\",\n      \"method\": \"Yeast two-hybrid screen, immuno-affinity chromatography, co-immunoprecipitation, Hsp90 inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional protein stability assay with multiple interactors\",\n      \"pmids\": [\"16919237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRMS1 contains a functional nuclear localization signal (NLS) sufficient for nuclear import that is mediated specifically by importin alpha6, and a CRM1-independent nuclear export signal; BRMS1 can shuttle between nuclear and cytoplasmic compartments.\",\n      \"method\": \"Nuclear import/export assays, yeast two-hybrid (importin alpha6 interaction), interspecies heterokaryon shuttling assay, leptomycin B treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional NLS/NES mapping with orthogonal localization assays and direct binding partner identification\",\n      \"pmids\": [\"19649328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal NLS2 (amino acids 238-244) of BRMS1 is necessary for metastasis suppression independent of nuclear localization; NLS2 enables cytoplasmic interaction with SIN3A and regulation of miR-10b, which are critical for metastasis suppression.\",\n      \"method\": \"NLS mutagenesis, co-immunoprecipitation, xenograft mouse metastasis model, miRNA expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function mutagenesis combined with in vivo metastasis model and molecular readouts\",\n      \"pmids\": [\"23390556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RelA/p65 (NF-κB) functions as a transcriptional repressor of BRMS1 by directly recruiting DNMT-1 to the BRMS1 promoter following TNF-induced phosphorylation of S276 on RelA/p65, leading to promoter methylation and transcriptional repression.\",\n      \"method\": \"Chromatin immunoprecipitation, methylation-specific PCR, luciferase reporter assay, co-immunoprecipitation, site-directed mutagenesis of S276, small-molecule inhibition of interacting domains\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, direct protein interaction, mutagenesis, and functional reporter assay with multiple orthogonal methods\",\n      \"pmids\": [\"21765477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of BRMS1 promotes epithelial-to-mesenchymal transition (EMT) in NSCLC through NF-κB (RelA/p65)-dependent upregulation of Twist1; BRMS1 loss increases RelA/p65 K310 acetylation-associated occupancy of the Twist1 promoter, and Twist1 knockdown reverses BRMS1 knockdown-induced EMT.\",\n      \"method\": \"shRNA knockdown, chromatin immunoprecipitation, EMT marker analysis, migration assay, in vivo tumor model with double knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with genetic epistasis (double knockdown rescue) and in vivo model\",\n      \"pmids\": [\"25368381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRMS1 attenuates TGF-β1-induced breast cancer cell invasion by downregulating HIF-1α transcript through NF-κB inactivation, which in turn reduces Snail and TWIST1 expression; ChIP and luciferase reporter assays validated HIF-1α as a transcriptional regulator of Snail and TWIST1 downstream of BRMS1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, quantitative RT-PCR, immunoblotting, Matrigel invasion assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay with functional invasion readout establish pathway positioning\",\n      \"pmids\": [\"26520789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JARID1C (a histone demethylase) promotes breast cancer metastasis by demethylating H3K4me3 at the BRMS1 gene promoter, leading to reduced BRMS1 expression; silencing JARID1C increases BRMS1 expression and inhibits cell migration and invasion.\",\n      \"method\": \"ChIP for H3K4me3, siRNA knockdown of JARID1C, qRT-PCR/western blot for BRMS1 expression, migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct histone modification at BRMS1 promoter with functional rescue\",\n      \"pmids\": [\"26182878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRMS1 expression reduces activation of β1 integrin and focal adhesion kinase (FAK) and their localization to focal adhesions, impairs cytoskeletal reorganization on collagen and fibronectin, and prevents invasive colony formation under 3D culture conditions, without altering integrin monomer expression levels.\",\n      \"method\": \"Time-lapse and confocal microscopy, integrin activation assays, 3D culture, FAK immunostaining\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization imaging with functional consequence in multiple assay conditions\",\n      \"pmids\": [\"24000122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-93-5p targets the 3'-UTR of BRMS1L mRNA, suppresses BRMS1L expression, promotes EMT (reducing E-cadherin, increasing N-cadherin), and activates Wnt signaling (increased TOP/FOP luciferase activity); re-expression of BRMS1L reverses miR-93-5p-driven invasiveness and reduces Wnt signaling.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR targeting), western blotting, EMT marker analysis, migration/invasion assays, TOP/FOP luciferase (Wnt activity)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — validated 3'-UTR targeting with functional rescue and pathway reporter assay\",\n      \"pmids\": [\"29760585\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRMS1L (breast cancer metastasis suppressor 1-like) is a component of the Sin3A-HDAC co-repressor complex that suppresses cancer cell invasion and metastasis by epigenetically silencing pro-metastatic target genes (e.g., FZD10) through HDAC1 recruitment and histone deacetylation, inhibiting Wnt/β-catenin signaling; it is transcriptionally induced by the p53 pathway, post-translationally regulated by ubiquitin-mediated degradation (via TRIM7), and its related family member BRMS1 undergoes CK2α'-mediated phosphorylation at S30 promoting nuclear export and proteasomal degradation, while also associating with LSD1/CoREST and SIN3 chromatin remodeling complexes to coordinately suppress metastasis-related gene expression and NF-κB/Twist1-driven EMT.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification notes:**\n- Papers about IL-12 p40, p40(phox), LBP-p40/37LRP, Lactobacillus p40, p63 isoform ΔNp63/p40, LINE-1 p40, AAV p40 promoter, Mycobacterium p40, etc. → EXCLUDE (alias collisions)\n- Papers about BRMS1 (the paralog) → EXCLUDE (different gene, not BRMS1L)\n- Papers about BRMS1L directly → KEEP\n- Large interactome/proteomics papers that identified BRMS1L as part of Sin3A/HDAC complex → KEEP if they provide mechanistic data about BRMS1L specifically\n\n**KEPT papers:**\n- PMID 25406648: BRMS1L/Sin3A-HDAC/FZD10/Wnt signaling — direct BRMS1L mechanism\n- PMID 28515442: BRMS1L identified as component of mSin3A/HDAC complex (paper 28 in retrieved = PMID 15451426 — describes \"p40\" as BRMS1L homologue, component of mSin3A complex)\n- PMID 29030916: BRMS1L as p53 target gene\n- PMID 29760585: miR-93-5p/BRMS1L/Wnt signaling in LACC\n- PMID 31298311: miR-934/BRMS1L in ovarian cancer\n- PMID 15451426: p40 identified as BRMS1L homologue, component of mSin3A/HDAC1 complex — KEEP\n- Large interactome papers (BioPlex etc.) — these don't describe BRMS1L-specific mechanistic findings, just list interactions; marginal but some identify Sin3A complex membership. I'll include BioPlex papers only if they specifically characterize BRMS1L interactions.\n\nAfter careful review, the BioPlex/interactome papers (PMIDs 26186194, 28514442, 26496610, 25416956, 32296183, 33961781) are large-scale screens without BRMS1L-specific mechanistic detail — I'll exclude from discoveries.\n\nFAM60A Sin3 paper (PMID 22984288) and ING paper (PMID 16387653) and HDAC interactome (PMID 23752268) don't specifically characterize BRMS1L mechanistically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"BRMS1L (referred to as 'p40') was identified as a novel component of the mSin3A/p33(ING1b)/HDAC1 histone deacetylase co-repressor complex by biochemical purification and mass spectrometry. The p40-associated complex showed strong HDAC activity, and when tethered to a Gal4 DNA-binding domain, Gal-p40 significantly repressed transcription of a Gal-luciferase reporter. BRMS1L bears homology to yeast Sds3 and mammalian mSds3, and overexpression inhibited cell growth.\",\n      \"method\": \"Biochemical purification, mass spectrometry, HDAC activity assay, Gal4-tethered transcriptional repression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification + MS + functional reporter assay, single study\",\n      \"pmids\": [\"15451426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRMS1L is a component of the Sin3A-HDAC co-repressor complex that suppresses breast cancer metastasis by epigenetically silencing FZD10 (a Wnt receptor) through HDAC1 recruitment and histone H3K9 deacetylation at the FZD10 promoter. This silencing inhibits aberrant WNT3-FZD10-β-catenin signalling and epithelial-mesenchymal transition. BRMS1L was also identified as a direct target of miR-106b, whose upregulation reduces BRMS1L levels in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay (H3K9 acetylation), luciferase reporter assay, siRNA knockdown, xenograft mouse model, miRNA target validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, luciferase, in vivo), single rigorous study with strong mechanistic support\",\n      \"pmids\": [\"25406648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRMS1L is a transcriptional target of p53 family proteins (p53, TAp63γ, TAp73β). Two p53 family response elements were identified in the first intron and upstream region of BRMS1L, conserved among mammals. Ectopic expression of BRMS1L inhibited cancer cell invasion and migration, while siRNA knockdown of BRMS1L induced the opposite effect, placing BRMS1L downstream of the p53 pathway in regulating cell invasion.\",\n      \"method\": \"Microarray analysis, luciferase reporter assay with response element mutations, siRNA knockdown, invasion/migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assays identifying response elements plus loss-of-function phenotype, single study\",\n      \"pmids\": [\"29030916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-93-5p promotes lacrimal gland adenoid cystic carcinoma (LACC) cell migration, invasion, and proliferation by directly targeting and suppressing BRMS1L expression. Luciferase reporter assays confirmed miR-93-5p binding to the BRMS1L 3'-UTR. BRMS1L overexpression inhibited EMT markers and suppressed Wnt signaling (reduced TOP/FOP luciferase activity), while miR-93-5p overexpression activated Wnt signaling in a BRMS1L-dependent manner.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR targeting), western blotting, qRT-PCR, wound healing/transwell assays, TOP/FOP Wnt reporter assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — validated miRNA-target relationship with functional rescue experiments, single study\",\n      \"pmids\": [\"29760585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-934 promotes ovarian cancer cell proliferation and inhibits apoptosis by targeting BRMS1L. Luciferase reporter assays confirmed direct miR-934 binding to BRMS1L mRNA. miR-934 inhibition increased BRMS1L expression, reduced Ki67 and Cyclin D1, and induced Caspase-3 activation, demonstrating BRMS1L's role in regulating the apoptosis/proliferation balance downstream of miR-934.\",\n      \"method\": \"Luciferase reporter assay, CCK-8 proliferation assay, TUNEL apoptosis assay, western blotting, qRT-PCR\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — validated miRNA-target binding with functional cellular phenotype, single study\",\n      \"pmids\": [\"31298311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRMS1L is a component of the Sin3A-HDAC co-repressor complex that suppresses cancer metastasis primarily through epigenetic silencing of pro-metastatic target genes (including FZD10) via HDAC1 recruitment and histone H3K9 deacetylation, thereby inhibiting Wnt/β-catenin signalling and EMT; its expression is regulated downstream of p53 family transcription factors and is post-transcriptionally repressed by multiple miRNAs including miR-106b, miR-93-5p, and miR-934.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BRMS1L and its paralog BRMS1 function as metastasis suppressors by serving as integral subunits of Sin3A/HDAC and LSD1/CoREST co-repressor complexes, where they epigenetically silence pro-metastatic target genes through histone deacetylation and demethylation [PMID:15451426, PMID:25406648, PMID:30416854]. BRMS1L silences FZD10 via HDAC1-mediated H3K9 deacetylation at the FZD10 promoter to inhibit WNT/β-catenin signaling, while BRMS1 suppresses NF-κB/Twist1-driven epithelial-to-mesenchymal transition, integrin/FAK activation, and HIF-1α-dependent invasion programs [PMID:25406648, PMID:25368381, PMID:24000122, PMID:26520789]. BRMS1L is transcriptionally activated by p53 family members and post-transcriptionally repressed by miR-106b and miR-93-5p, whereas BRMS1 is transcriptionally silenced by NF-κB-recruited DNMT1 promoter methylation and post-translationally destabilized by CK2α′-triggered nuclear export and ubiquitin-proteasome degradation mediated by TRIM7 and Cul3-SPOP E3 ligases [PMID:29030916, PMID:29760585, PMID:21765477, PMID:26980766, PMID:32853985, PMID:22085717]. A germline variant (A273V) in BRMS1 abolishes its interaction with nuclear Src, derepressing c-fos/CEACAM6-driven metastasis in lung adenocarcinoma [PMID:36197962].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of BRMS1L (p40) as a novel Sin3A/HDAC complex subunit established it as a transcriptional co-repressor with growth-inhibitory function, providing the first mechanistic framework for the gene.\",\n      \"evidence\": \"Biochemical purification with mass spectrometry, Gal4-tethering reporter assay, and cell growth assay in human cells\",\n      \"pmids\": [\"15451426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BRMS1L-specific chromatin targets not identified\", \"relationship to metastasis not yet established\", \"contribution relative to other Sin3A subunits unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that BRMS1 interacts with class II HDACs and chaperones (Hsp90, DNAJB6) and undergoes proteasome-dependent turnover stabilized by Hsp90 revealed that the protein is dynamically regulated at the post-translational level.\",\n      \"evidence\": \"Yeast two-hybrid, immuno-affinity chromatography, Co-IP, Hsp90 inhibitor treatment in human cells\",\n      \"pmids\": [\"16919237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase responsible for BRMS1 turnover not identified at this stage\", \"functional significance of class II HDAC interactions for metastasis not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping of a functional NLS recognized by importin-α6 and a CRM1-independent NES demonstrated that BRMS1 shuttles between nucleus and cytoplasm, raising the question of whether its anti-metastatic activity requires nuclear residence.\",\n      \"evidence\": \"Nuclear import/export assays, heterokaryon shuttling, leptomycin B treatment, yeast two-hybrid for importin-α6\",\n      \"pmids\": [\"19649328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether nucleocytoplasmic shuttling is regulated by signaling cues not determined\", \"BRMS1L-specific shuttling not examined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies resolved how BRMS1 is itself transcriptionally silenced and post-translationally degraded: TNF-activated NF-κB (RelA/p65 pS276) recruits DNMT1 to methylate and silence the BRMS1 promoter, while the Cul3-SPOP E3 ligase ubiquitinates BRMS1 for proteasomal degradation.\",\n      \"evidence\": \"ChIP, methylation-specific PCR, luciferase reporter, mutagenesis (RelA S276); Co-IP, ubiquitination assay, siRNA knockdown (SPOP)\",\n      \"pmids\": [\"21765477\", \"22085717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNMT1-mediated silencing also applies to BRMS1L promoter unknown\", \"SPOP-dependent degradation not tested in vivo metastasis models\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structure–function analysis showed the C-terminal NLS2 of BRMS1 is essential for metastasis suppression not through nuclear import but through enabling cytoplasmic SIN3A interaction and miR-10b regulation, while separate work demonstrated BRMS1 dampens β1-integrin activation and FAK signaling at focal adhesions.\",\n      \"evidence\": \"NLS mutagenesis with Co-IP and xenograft metastasis model; confocal microscopy, integrin activation assays, and 3D culture\",\n      \"pmids\": [\"23390556\", \"24000122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoplasmic SIN3A-BRMS1 complex stoichiometry not resolved\", \"mechanism connecting BRMS1 to integrin activation state is indirect\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"BRMS1L was directly linked to metastasis suppression: it silences FZD10 through HDAC1 recruitment and H3K9 deacetylation, blocking WNT3-FZD10-β-catenin signaling; concurrently, BRMS1 loss was shown to drive EMT via NF-κB-dependent Twist1 upregulation.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase reporter, RNAi, xenograft model (BRMS1L–FZD10 axis); shRNA, ChIP, EMT marker analysis, double-knockdown rescue in vivo (BRMS1–Twist1 axis)\",\n      \"pmids\": [\"25406648\", \"25368381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRMS1L also regulates NF-κB/Twist1 axis not tested\", \"genome-wide BRMS1L ChIP-seq targets not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Upstream epigenetic regulation of BRMS1 was established: JARID1C demethylates H3K4me3 at the BRMS1 promoter to repress it, and BRMS1 itself attenuates TGF-β1-induced invasion by NF-κB-dependent downregulation of HIF-1α/Snail/TWIST1.\",\n      \"evidence\": \"ChIP for H3K4me3, siRNA, qRT-PCR, western blot, migration/invasion assays (JARID1C); ChIP, luciferase reporter, invasion assay (HIF-1α axis)\",\n      \"pmids\": [\"26182878\", \"26520789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JARID1C also regulates BRMS1L not examined\", \"in vivo validation of HIF-1α pathway link lacking\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CK2α′-mediated phosphorylation of BRMS1 at S30 was identified as a TNF-induced switch that promotes 14-3-3ε binding, nuclear export, and ubiquitin-proteasome degradation, establishing a signaling mechanism by which the tumor microenvironment neutralizes the metastasis suppressor.\",\n      \"evidence\": \"Site-directed mutagenesis, Co-IP, orthotopic mouse metastasis model, CK2 inhibitor CX4945, human NSCLC tissue analysis\",\n      \"pmids\": [\"26980766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether analogous phosphorylation regulates BRMS1L not tested\", \"identity of ubiquitin ligase downstream of CK2α′-triggered export not determined in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"BRMS1L was placed downstream of the p53 tumor suppressor pathway: p53, TAp63γ, and TAp73β directly transactivate BRMS1L through two intronic/upstream response elements, connecting genomic integrity surveillance to metastasis suppression.\",\n      \"evidence\": \"Microarray, luciferase reporter with response element mapping, ectopic expression and siRNA with invasion/migration assays\",\n      \"pmids\": [\"29030916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous p53 ChIP at BRMS1L locus not shown\", \"functional relevance in p53-mutant cancers not explored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"BRMS1 was shown to be an integral subunit of the LSD1/CoREST co-repressor complex, broadening its co-repressor repertoire beyond Sin3A/HDAC; separately, miR-93-5p was validated as a post-transcriptional repressor of BRMS1L that activates Wnt signaling and EMT.\",\n      \"evidence\": \"Affinity purification/MS, RNA-seq, Co-IP, migration/invasion assays (LSD1/CoREST); 3′-UTR luciferase reporter, TOP/FOP Wnt reporter, EMT marker analysis, rescue (miR-93-5p)\",\n      \"pmids\": [\"30416854\", \"29760585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BRMS1L also integrates into LSD1/CoREST not tested\", \"genome-wide target overlap between Sin3A and LSD1/CoREST complexes not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TRIM7 was identified as an E3 ubiquitin ligase for BRMS1, linking its degradation to osteosarcoma chemoresistance and providing a second defined ubiquitin ligase (alongside Cul3-SPOP) that targets the BRMS1 family.\",\n      \"evidence\": \"Co-IP, mass spectrometry, pulldown, ubiquitination assay, immunofluorescence in osteosarcoma cells\",\n      \"pmids\": [\"32853985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM7 also ubiquitinates BRMS1L not examined\", \"in vivo validation of TRIM7-BRMS1 axis in metastasis models lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A germline SNP (A273V) in BRMS1 was shown to abolish interaction with nuclear Src, derepress c-fos transcription, upregulate CEACAM6, and drive lung adenocarcinoma metastasis, establishing a clinically actionable genetic variant that disables metastasis suppression.\",\n      \"evidence\": \"NGS, Co-IP, invasion assays, tail-vein xenograft, patient-derived organoid intracardiac injection models, c-fos inhibitor T5224\",\n      \"pmids\": [\"36197962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Src–BRMS1 interaction disruption by A273V not resolved\", \"frequency and penetrance of rs1052566 across populations not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether BRMS1L undergoes the same post-translational regulatory mechanisms (CK2α′ phosphorylation, TRIM7/SPOP ubiquitination) as BRMS1, the genome-wide direct chromatin targets of BRMS1L, and the structural basis for BRMS1L integration into co-repressor complexes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No BRMS1L-specific ChIP-seq or CUT&RUN data reported\", \"No structural model of BRMS1L within Sin3A/HDAC complex\", \"Post-translational regulation of BRMS1L (ubiquitination, phosphorylation) not directly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [\n      \"Sin3A/HDAC co-repressor complex\",\n      \"LSD1/CoREST co-repressor complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"LSD1\",\n      \"SPOP\",\n      \"TRIM7\",\n      \"CSNK2A2\",\n      \"YWHAE\",\n      \"KPNA5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"BRMS1L is a subunit of the Sin3A–HDAC co-repressor complex that functions as a metastasis suppressor by mediating epigenetic silencing of pro-metastatic target genes [PMID:15451426, PMID:25406648]. It recruits HDAC1 to the FZD10 promoter, driving histone H3K9 deacetylation that silences FZD10 transcription and thereby inhibits WNT3–β-catenin signalling and epithelial-mesenchymal transition in breast cancer cells [PMID:25406648]. BRMS1L expression is transcriptionally activated by p53 family members (p53, TAp63γ, TAp73β) through conserved intronic and upstream response elements, and is post-transcriptionally repressed by miR-106b, miR-93-5p, and miR-934, linking its anti-metastatic activity to both tumour-suppressor and miRNA regulatory networks [PMID:29030916, PMID:25406648, PMID:29760585, PMID:31298311].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of BRMS1L as a stoichiometric component of the mSin3A/HDAC1 co-repressor complex established its molecular context as an HDAC-associated transcriptional co-repressor rather than a stand-alone DNA-binding factor.\",\n      \"evidence\": \"Biochemical purification and mass spectrometry of endogenous mSin3A complexes, Gal4-tethered repression reporter assay, HeLa cells\",\n      \"pmids\": [\"15451426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without reciprocal pull-down from BRMS1L bait\",\n        \"Direct chromatin targets of BRMS1L-containing complexes not identified\",\n        \"Whether BRMS1L is required for complex integrity or is an accessory subunit is unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting BRMS1L's co-repressor activity to a specific metastasis-relevant pathway resolved how it suppresses breast cancer metastasis: BRMS1L recruits HDAC1 to the FZD10 promoter, deacetylates H3K9, silences FZD10, and thereby blocks Wnt/β-catenin-driven EMT.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP for H3K9ac at FZD10 promoter, siRNA knockdown, luciferase reporters, xenograft metastasis model in mice, miR-106b target validation, breast cancer cell lines\",\n      \"pmids\": [\"25406648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genome-wide binding profile of BRMS1L is unknown; FZD10 may not be the sole critical target\",\n        \"Whether BRMS1L loss is sufficient for metastasis in immunocompetent models is untested\",\n        \"Structural basis for BRMS1L–HDAC1 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that BRMS1L is a direct transcriptional target of p53, TAp63γ, and TAp73β placed it within the p53 tumour-suppressor axis, explaining how upstream tumour-suppressive signals converge on BRMS1L-mediated metastasis inhibition.\",\n      \"evidence\": \"Microarray screen, luciferase reporter assays with response-element mutations in BRMS1L intron 1 and upstream region, siRNA knockdown invasion/migration assays, cancer cell lines\",\n      \"pmids\": [\"29030916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ChIP confirmation of endogenous p53-family occupancy at BRMS1L locus not shown\",\n        \"Relative contribution of each p53 family member under physiological conditions is unclear\",\n        \"Whether p53-dependent regulation is context-specific (e.g. tissue-type) is not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Validation of miR-93-5p as a second miRNA repressor of BRMS1L in adenoid cystic carcinoma extended the miRNA-BRMS1L-Wnt axis beyond breast cancer, reinforcing BRMS1L as a general gatekeeper of Wnt/β-catenin activation across tumour types.\",\n      \"evidence\": \"3′-UTR luciferase reporter, TOP/FOP Wnt reporter, rescue by BRMS1L re-expression, LACC cell lines\",\n      \"pmids\": [\"29760585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cancer type without in vivo validation\",\n        \"Whether miR-93-5p operates through BRMS1L in normal lacrimal tissue is unknown\",\n        \"Downstream Wnt target gene specificity not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of miR-934 as a third miRNA targeting BRMS1L in ovarian cancer linked BRMS1L loss to both increased proliferation and reduced apoptosis, broadening its tumour-suppressive functions beyond EMT/metastasis.\",\n      \"evidence\": \"3′-UTR luciferase reporter, CCK-8 proliferation, TUNEL apoptosis assay, western blot for Ki67/CyclinD1/Caspase-3, ovarian cancer cell lines\",\n      \"pmids\": [\"31298311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study in one journal without in vivo confirmation\",\n        \"Mechanism by which BRMS1L regulates apoptosis (direct target genes) is not delineated\",\n        \"Specificity of miR-934 effect — other targets may contribute to the phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide repertoire of BRMS1L-regulated loci, the structural basis of its integration into the Sin3A–HDAC complex, and its physiological role in non-cancer contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genome-wide ChIP-seq or CUT&Tag profiling of BRMS1L\",\n        \"No structural or cryo-EM data for BRMS1L within the Sin3A complex\",\n        \"No genetic mouse model (knockout or conditional) characterising BRMS1L loss in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0004839\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Sin3A-HDAC co-repressor complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"ING1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I notice I included an erroneous pathway entry (`GO:0004839` which is not a valid Reactome ID and has no supporting discoveries). Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"BRMS1L is a subunit of the Sin3A–HDAC co-repressor complex that functions as a metastasis suppressor by mediating epigenetic silencing of pro-metastatic target genes [PMID:15451426, PMID:25406648]. It recruits HDAC1 to the FZD10 promoter, driving histone H3K9 deacetylation that silences FZD10 transcription and thereby inhibits WNT3–β-catenin signalling and epithelial-mesenchymal transition in breast cancer cells [PMID:25406648]. BRMS1L expression is transcriptionally activated by p53 family members (p53, TAp63γ, TAp73β) through conserved intronic and upstream response elements, and is post-transcriptionally repressed by miR-106b, miR-93-5p, and miR-934, linking its anti-metastatic activity to both tumour-suppressor and miRNA regulatory networks [PMID:29030916, PMID:25406648, PMID:29760585, PMID:31298311].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of BRMS1L as a stoichiometric component of the mSin3A/HDAC1 co-repressor complex established its molecular context as an HDAC-associated transcriptional co-repressor rather than a stand-alone DNA-binding factor.\",\n      \"evidence\": \"Biochemical purification and mass spectrometry of endogenous mSin3A complexes, Gal4-tethered repression reporter assay, HeLa cells\",\n      \"pmids\": [\"15451426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without reciprocal pull-down from BRMS1L bait\",\n        \"Direct chromatin targets of BRMS1L-containing complexes not identified\",\n        \"Whether BRMS1L is required for complex integrity or is an accessory subunit is unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting BRMS1L's co-repressor activity to a specific metastasis-relevant pathway resolved how it suppresses breast cancer metastasis: BRMS1L recruits HDAC1 to the FZD10 promoter, deacetylates H3K9, silences FZD10, and thereby blocks Wnt/β-catenin-driven EMT.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP for H3K9ac at FZD10 promoter, siRNA knockdown, luciferase reporters, xenograft metastasis model in mice, miR-106b target validation, breast cancer cell lines\",\n      \"pmids\": [\"25406648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genome-wide binding profile of BRMS1L is unknown; FZD10 may not be the sole critical target\",\n        \"Whether BRMS1L loss is sufficient for metastasis in immunocompetent models is untested\",\n        \"Structural basis for BRMS1L–HDAC1 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that BRMS1L is a direct transcriptional target of p53, TAp63γ, and TAp73β placed it within the p53 tumour-suppressor axis, explaining how upstream tumour-suppressive signals converge on BRMS1L-mediated metastasis inhibition.\",\n      \"evidence\": \"Microarray screen, luciferase reporter assays with response-element mutations in BRMS1L intron 1 and upstream region, siRNA knockdown invasion/migration assays, cancer cell lines\",\n      \"pmids\": [\"29030916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ChIP confirmation of endogenous p53-family occupancy at BRMS1L locus not shown\",\n        \"Relative contribution of each p53 family member under physiological conditions is unclear\",\n        \"Whether p53-dependent regulation is context-specific to certain tissue types is not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Validation of miR-93-5p as a second miRNA repressor of BRMS1L in adenoid cystic carcinoma extended the miRNA–BRMS1L–Wnt axis beyond breast cancer, reinforcing BRMS1L as a general gatekeeper of Wnt/β-catenin activation across tumour types.\",\n      \"evidence\": \"3′-UTR luciferase reporter, TOP/FOP Wnt reporter, rescue by BRMS1L re-expression, LACC cell lines\",\n      \"pmids\": [\"29760585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cancer type without in vivo validation\",\n        \"Whether miR-93-5p operates through BRMS1L in normal lacrimal tissue is unknown\",\n        \"Downstream Wnt target gene specificity not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of miR-934 as a third miRNA targeting BRMS1L in ovarian cancer linked BRMS1L loss to both increased proliferation and reduced apoptosis, broadening its tumour-suppressive functions beyond EMT and metastasis.\",\n      \"evidence\": \"3′-UTR luciferase reporter, CCK-8 proliferation, TUNEL apoptosis assay, western blot for Ki67/CyclinD1/Caspase-3, ovarian cancer cell lines\",\n      \"pmids\": [\"31298311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without in vivo confirmation\",\n        \"Mechanism by which BRMS1L regulates apoptosis (direct target genes) is not delineated\",\n        \"Specificity of miR-934 effect — other miR-934 targets may contribute to the phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide repertoire of BRMS1L-regulated loci, the structural basis of its integration into the Sin3A–HDAC complex, and its physiological role in non-cancer contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genome-wide ChIP-seq or CUT&Tag profiling of BRMS1L\",\n        \"No structural or cryo-EM data for BRMS1L within the Sin3A complex\",\n        \"No genetic mouse model (knockout or conditional) characterising BRMS1L loss in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Sin3A-HDAC co-repressor complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"ING1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}