{"gene":"ARMC6","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2018,"finding":"Human ARMC6 (the putative homolog of Arabidopsis ARM protein) co-precipitates telomerase activity and interacts with the human shelterin protein hTRF2 in vitro, suggesting a role in telomere-associated or non-canonical telomerase pathways.","method":"Co-immunoprecipitation (telomerase activity co-precipitation) and in vitro protein-protein interaction assay","journal":"Plant molecular biology","confidence":"Low","confidence_rationale":"Tier 3 — single in vitro pulldown/co-precipitation, single study, limited follow-up on human ARMC6 specifically","pmids":["29948659"],"is_preprint":false},{"year":2024,"finding":"Human ARMC6 binds in vitro to G-quadruplex-forming DNA sequences from promoters of cancer-related genes (EGFR, VEGF, c-MYC) and to telomeric repeat-containing RNA (TERRA), with preferential binding to RNA over DNA G-quadruplex structures, implicating ARMC6 as a G-quadruplex structure recognition protein.","method":"In vitro binding assays (electrophoretic mobility shift assay and related biochemical binding experiments) with recombinant ARMC6 protein against G-quadruplex DNA/RNA substrates; overexpression in human cell lines with downstream gene expression analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple in vitro binding experiments with defined substrates, functional overexpression data in human cells; single lab, single study","pmids":["39029558"],"is_preprint":false},{"year":2025,"finding":"ARMC6 is a substrate of the human protein histidine methyltransferase METTL9, which generates 1-methylhistidine (π-methylhistidine) at histidine-x-histidine (HxH) motifs within ARMC6; ARMC6 serves as a prototype substrate for defining METTL9 activity and substrate specificity across species.","method":"In vitro methyltransferase assay using recombinant proteins and peptides; mass spectrometry to detect methylation; mutagenesis of substrate motifs; cross-species ortholog comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant enzyme and substrate, peptide-level validation, mass spectrometric confirmation of modification site","pmids":["40451431"],"is_preprint":false}],"current_model":"ARMC6 is an armadillo-repeat protein that interacts with the shelterin component hTRF2 and co-precipitates telomerase activity; it preferentially binds G-quadruplex RNA/DNA structures (including TERRA and cancer gene promoters) in vitro, suggesting a role at the interface of telomere biology and gene regulation; additionally, ARMC6 is a substrate of the protein histidine methyltransferase METTL9, which methylates it at HxH motifs to generate 1-methylhistidine, placing ARMC6 in the emerging landscape of protein histidine methylation."},"narrative":{"teleology":[{"year":2018,"claim":"The first indication that ARMC6 participates in telomere biology came from its co-precipitation with telomerase activity and physical interaction with the shelterin protein TRF2, suggesting it operates in telomere-associated pathways.","evidence":"Co-immunoprecipitation of telomerase activity and in vitro protein–protein interaction assay with human ARMC6 and TRF2","pmids":["29948659"],"confidence":"Low","gaps":["Single in vitro pulldown without reciprocal validation or in-cell confirmation","No evidence that ARMC6 localizes to telomeres in cells","Functional consequence of ARMC6–TRF2 interaction undefined"]},{"year":2024,"claim":"Identification of ARMC6 as a G-quadruplex recognition protein explained a potential molecular basis for its telomeric and gene-regulatory associations, showing it preferentially binds RNA over DNA G-quadruplex structures including TERRA and cancer gene promoter sequences.","evidence":"Electrophoretic mobility shift assays and biochemical binding experiments with recombinant ARMC6 and defined G-quadruplex substrates; overexpression in human cell lines with downstream gene expression analysis","pmids":["39029558"],"confidence":"Medium","gaps":["In vivo binding targets not mapped (e.g., no CLIP or ChIP-seq)","Whether G-quadruplex binding is mediated by the armadillo repeats or another domain is unresolved","Physiological consequences of G-quadruplex binding on gene expression or telomere maintenance not established in loss-of-function studies"]},{"year":2025,"claim":"Demonstration that ARMC6 is methylated at HxH motifs by METTL9 established it as a bona fide substrate of protein histidine methylation, raising the question of whether this modification regulates its G-quadruplex binding or protein interactions.","evidence":"In vitro methyltransferase assay with recombinant METTL9 and ARMC6, mass spectrometric identification of 1-methylhistidine, mutagenesis of HxH motifs","pmids":["40451431"],"confidence":"High","gaps":["Whether ARMC6 is methylated by METTL9 in cells has not been shown","Functional impact of histidine methylation on ARMC6 activity, stability, or binding is unknown","Stoichiometry of modification in vivo is undefined"]},{"year":null,"claim":"The cellular function of ARMC6 remains poorly defined: it is unclear whether its G-quadruplex binding and telomere-associated interactions reflect a single unified role or distinct activities, and no loss-of-function phenotype has been reported.","evidence":"","pmids":[],"confidence":"Low","gaps":["No knockout or knockdown phenotypic data available","No genome-wide binding profile (ChIP-seq, CLIP) to define in vivo targets","Relationship between METTL9-mediated methylation and G-quadruplex/telomere functions untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1]}],"localization":[],"pathway":[],"complexes":[],"partners":["TRF2","METTL9"],"other_free_text":[]},"mechanistic_narrative":"ARMC6 is an armadillo repeat-containing protein that binds G-quadruplex-forming DNA and RNA structures in vitro, with preferential affinity for RNA G-quadruplexes including the telomeric repeat-containing RNA TERRA and G-quadruplex sequences from cancer gene promoters (EGFR, VEGF, c-MYC) [PMID:39029558]. ARMC6 co-precipitates telomerase activity and interacts with the shelterin component TRF2, placing it at the interface of telomere biology [PMID:29948659]. ARMC6 is a substrate of the protein histidine methyltransferase METTL9, which generates 1-methylhistidine at HxH motifs within ARMC6, establishing it as a defined target of this post-translational modification [PMID:40451431]."},"prefetch_data":{"uniprot":{"accession":"Q6NXE6","full_name":"Armadillo repeat-containing protein 6","aliases":[],"length_aa":501,"mass_kda":54.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6NXE6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMC6","classification":"Not Classified","n_dependent_lines":359,"n_total_lines":1208,"dependency_fraction":0.29718543046357615},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARMC6","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":111.9}],"url":"https://www.proteinatlas.org/search/ARMC6"},"hgnc":{"alias_symbol":["MGC19595"],"prev_symbol":[]},"alphafold":{"accession":"Q6NXE6","domains":[{"cath_id":"1.10.10","chopping":"30-89","consensus_level":"medium","plddt":89.1433,"start":30,"end":89},{"cath_id":"1.20.58","chopping":"275-368","consensus_level":"medium","plddt":94.8579,"start":275,"end":368},{"cath_id":"1.25.40","chopping":"383-390_404-487","consensus_level":"medium","plddt":96.105,"start":383,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NXE6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NXE6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NXE6-F1-predicted_aligned_error_v6.png","plddt_mean":90.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMC6","jax_strain_url":"https://www.jax.org/strain/search?query=ARMC6"},"sequence":{"accession":"Q6NXE6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NXE6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NXE6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NXE6"}},"corpus_meta":[{"pmid":"29948659","id":"PMC_29948659","title":"An armadillo-domain protein participates in a telomerase interaction network.","date":"2018","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29948659","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38572415","id":"PMC_38572415","title":"The genetic landscape of autism spectrum disorder in the Middle Eastern population.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38572415","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30292870","id":"PMC_30292870","title":"Molecular cloning, characterization and expression analysis of ARMC6, ARMC7, ARMC8 from Pacific white shrimp, Litopenaeus vannamei.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30292870","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40451431","id":"PMC_40451431","title":"Orthologues of the human protein histidine methyltransferase METTL9 display distinct substrate specificities.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40451431","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39029558","id":"PMC_39029558","title":"Human ARMC6 binds in vitro to both cancer genes and telomeric RNA, favoring G-quadruplex structure recognition.","date":"2024","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/39029558","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37414911","id":"PMC_37414911","title":"Genome-wide DNA methylation analysis in schizophrenia with tardive dyskinesia: a preliminary study.","date":"2023","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37414911","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15057824","id":"PMC_15057824","title":"The DNA sequence and biology of human chromosome 19.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15057824","citation_count":271,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8895530","id":"PMC_8895530","title":"A pancreatic cancer-specific expression profile.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8895530","citation_count":151,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25609649","id":"PMC_25609649","title":"Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.","date":"2015","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/25609649","citation_count":120,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31753913","id":"PMC_31753913","title":"Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/31753913","citation_count":110,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30442662","id":"PMC_30442662","title":"Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30442662","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33545068","id":"PMC_33545068","title":"Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33545068","citation_count":105,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24797263","id":"PMC_24797263","title":"Proteomic analysis of the epidermal growth factor receptor (EGFR) interactome and post-translational modifications associated with receptor endocytosis in response to EGF and stress.","date":"2014","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/24797263","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26972000","id":"PMC_26972000","title":"Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26972000","citation_count":77,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31586073","id":"PMC_31586073","title":"The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31586073","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35831314","id":"PMC_35831314","title":"Scalable multiplex co-fractionation/mass spectrometry platform for accelerated protein interactome discovery.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35831314","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31980649","id":"PMC_31980649","title":"Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31980649","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20811636","id":"PMC_20811636","title":"The protein network surrounding the human telomere repeat binding factors TRF1, TRF2, and POT1.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20811636","citation_count":51,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25192599","id":"PMC_25192599","title":"Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways.","date":"2014","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/25192599","citation_count":46,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25515538","id":"PMC_25515538","title":"A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25515538","citation_count":46,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31091453","id":"PMC_31091453","title":"PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31091453","citation_count":42,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23464991","id":"PMC_23464991","title":"Drafting the CLN3 protein interactome in SH-SY5Y human neuroblastoma cells: a label-free quantitative proteomics approach.","date":"2013","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/23464991","citation_count":40,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30349055","id":"PMC_30349055","title":"Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30349055","citation_count":37,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32994395","id":"PMC_32994395","title":"Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32994395","citation_count":36,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30884312","id":"PMC_30884312","title":"PRISMA: Protein Interaction Screen on Peptide Matrix Reveals Interaction Footprints and Modifications- Dependent Interactome of Intrinsically Disordered C/EBPβ.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30884312","citation_count":35,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30463901","id":"PMC_30463901","title":"BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/30463901","citation_count":32,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4873,"output_tokens":922,"usd":0.014224},"stage2":{"model":"claude-opus-4-6","input_tokens":4121,"output_tokens":1360,"usd":0.081907},"total_usd":0.213932,"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":17564,"output_tokens":1807,"usd":0.039899},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4322,"output_tokens":1213,"usd":0.077902}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Human ARMC6 interacts with hTRF2 (telomeric shelterin protein) in vitro and co-precipitates telomerase activity, suggesting participation in a telomerase interaction network.\",\n      \"method\": \"Co-immunoprecipitation (in vitro), co-precipitation of telomerase activity\",\n      \"journal\": \"Plant molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/co-IP, single lab, no functional follow-up for human ARMC6 specifically\",\n      \"pmids\": [\"29948659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ARMC6 binds in vitro to G-quadruplex DNA structures in promoter regions of cancer-related genes (EGFR, VEGF, c-MYC) and to telomeric RNA (TERRA), with preferential binding to RNA G-quadruplexes over DNA G-quadruplexes.\",\n      \"method\": \"In vitro DNA/RNA binding assays, G-quadruplex structure recognition assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assays with multiple substrates and structural motif specificity, single lab\",\n      \"pmids\": [\"39029558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of ARMC6 in human cell lines alters expression of genes connected with oncogenic and non-canonical telomerase pathways (VEGF, hTERT, c-MYC, ESM1, MMP3), indicating a regulatory role in gene expression downstream of G-quadruplex binding.\",\n      \"method\": \"Overexpression in human cell lines with gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression with transcriptional readout but no direct mechanistic pathway placement\",\n      \"pmids\": [\"39029558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARMC6 is a substrate of the human protein histidine methyltransferase METTL9, which methylates histidine residues within HxH motifs (generating 1-methylhistidine) in ARMC6 in vitro.\",\n      \"method\": \"In vitro methyltransferase assay with recombinant proteins and peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with recombinant proteins and peptide substrates, single lab but clear biochemical demonstration\",\n      \"pmids\": [\"40451431\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC6 is a conserved armadillo repeat-containing protein that interacts with the shelterin component hTRF2 and co-precipitates telomerase activity; it binds G-quadruplex nucleic acid structures (preferentially RNA over DNA) including TERRA and cancer gene promoters, and modulates expression of oncogenic and telomerase-related genes upon overexpression; additionally, ARMC6 serves as a substrate for the histidine methyltransferase METTL9, which methylates it at HxH motifs.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers.\n\n**Classification:**\n\n**Retrieved Papers:**\n1. PMID:29948659 — Arabidopsis ARM protein / human ARMC6 interaction with hTRF2. KEEP (describes human ARMC6 interaction with hTRF2 in vitro).\n2. PMID:38572415 — ASD genetics, ARMC6 mentioned as novel de novo variant candidate. EXCLUDE (no mechanistic finding, purely genetic/association).\n3. PMID:30292870 — Shrimp LvARMC6 characterization. EXCLUDE (invertebrate characterization with no functional mechanism relevant to human ARMC6; expression profiling only).\n4. PMID:40451431 — METTL9 methylates ARMC6 as substrate. KEEP (ARMC6 identified as substrate of METTL9 methyltransferase).\n5. PMID:39029558 — Human ARMC6 binds G-quadruplex DNA/RNA. KEEP (direct in vitro binding experiments on human ARMC6).\n6. PMID:37414911 — DNA methylation in schizophrenia/TD; ARMC6 mentioned as methylated gene. EXCLUDE (no mechanistic finding about ARMC6 protein).\n\n**Gene2pubmed Papers:**\n- PMID:28514442 (BioPlex 2.0), PMID:26496610 (HeLa interactome), PMID:17353931 (large-scale MS), PMID:33961781 (BioPlex 3.0), PMID:26344197 (metazoan complexes), PMID:25609649 (TF complexes), PMID:31753913 (BRD proteins), PMID:30442662 (UBQLN2/FUS), PMID:33545068 (autophagy receptors), PMID:24797263 (EGFR interactome), PMID:26972000 (PHD3/FIH substrates), PMID:31586073 (midbody interactome), PMID:35256949 (Parkin/HDAC), PMID:35831314 (mCF/MS), PMID:31980649 (KRAS/EGFR), PMID:20811636 (TRF1/TRF2/POT1 network), PMID:25192599 (FUS interactome), PMID:25515538 (SCFβTrCP), PMID:31091453 (PLEKHA4/Wnt), PMID:23464991 (CLN3), PMID:30349055 (17p/POLR2A), PMID:32994395 (OGT/XIAP), PMID:30884312 (C/EBPβ), PMID:30463901 (BAP1/NCoR1) — all large-scale interactome/proteomics studies or unrelated mechanistic papers. ARMC6 may appear incidentally in datasets but no specific mechanistic finding about ARMC6 is described in the abstracts. EXCLUDE.\n- PMID:12477932, PMID:15489334 — MGC cDNA sequencing projects. EXCLUDE (no mechanistic finding).\n- PMID:21873635 — GO propagation. EXCLUDE.\n- PMID:15057824 — Chr19 sequence. EXCLUDE.\n- PMID:8895530 — Pancreatic cancer expression profile. EXCLUDE.\n\n**KEEP papers with mechanistic content:** PMID:29948659, PMID:40451431, PMID:39029558.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Human ARMC6 (the putative homolog of Arabidopsis ARM protein) co-precipitates telomerase activity and interacts with the human shelterin protein hTRF2 in vitro, suggesting a role in telomere-associated or non-canonical telomerase pathways.\",\n      \"method\": \"Co-immunoprecipitation (telomerase activity co-precipitation) and in vitro protein-protein interaction assay\",\n      \"journal\": \"Plant molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single in vitro pulldown/co-precipitation, single study, limited follow-up on human ARMC6 specifically\",\n      \"pmids\": [\"29948659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ARMC6 binds in vitro to G-quadruplex-forming DNA sequences from promoters of cancer-related genes (EGFR, VEGF, c-MYC) and to telomeric repeat-containing RNA (TERRA), with preferential binding to RNA over DNA G-quadruplex structures, implicating ARMC6 as a G-quadruplex structure recognition protein.\",\n      \"method\": \"In vitro binding assays (electrophoretic mobility shift assay and related biochemical binding experiments) with recombinant ARMC6 protein against G-quadruplex DNA/RNA substrates; overexpression in human cell lines with downstream gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple in vitro binding experiments with defined substrates, functional overexpression data in human cells; single lab, single study\",\n      \"pmids\": [\"39029558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARMC6 is a substrate of the human protein histidine methyltransferase METTL9, which generates 1-methylhistidine (π-methylhistidine) at histidine-x-histidine (HxH) motifs within ARMC6; ARMC6 serves as a prototype substrate for defining METTL9 activity and substrate specificity across species.\",\n      \"method\": \"In vitro methyltransferase assay using recombinant proteins and peptides; mass spectrometry to detect methylation; mutagenesis of substrate motifs; cross-species ortholog comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant enzyme and substrate, peptide-level validation, mass spectrometric confirmation of modification site\",\n      \"pmids\": [\"40451431\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC6 is an armadillo-repeat protein that interacts with the shelterin component hTRF2 and co-precipitates telomerase activity; it preferentially binds G-quadruplex RNA/DNA structures (including TERRA and cancer gene promoters) in vitro, suggesting a role at the interface of telomere biology and gene regulation; additionally, ARMC6 is a substrate of the protein histidine methyltransferase METTL9, which methylates it at HxH motifs to generate 1-methylhistidine, placing ARMC6 in the emerging landscape of protein histidine methylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARMC6 is an armadillo repeat-containing protein that binds G-quadruplex nucleic acid structures, with preferential affinity for RNA G-quadruplexes including telomeric repeat-containing RNA (TERRA) and G-quadruplexes in promoter regions of cancer-related genes such as EGFR, VEGF, and c-MYC [PMID:39029558]. ARMC6 interacts with the shelterin component hTRF2 and co-precipitates telomerase activity, implicating it in telomere-associated complexes [PMID:29948659]. ARMC6 is a substrate of the histidine methyltransferase METTL9, which methylates its HxH motifs to generate 1-methylhistidine [PMID:40451431].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that ARMC6, previously uncharacterized in human cells, physically associates with the shelterin protein hTRF2 and co-precipitates telomerase activity placed it within the telomere maintenance network for the first time.\",\n      \"evidence\": \"Co-immunoprecipitation and telomerase activity co-precipitation assays in vitro\",\n      \"pmids\": [\"29948659\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single co-IP without reciprocal validation or in vivo confirmation\",\n        \"No determination of whether ARMC6 directly contacts telomerase or associates indirectly through hTRF2\",\n        \"Functional consequence of the hTRF2 interaction on telomere biology is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that ARMC6 directly binds G-quadruplex structures—preferentially RNA over DNA—including TERRA and oncogene promoter G-quadruplexes, provided a molecular activity that could explain its telomeric association and suggested a broader role in G-quadruplex-mediated gene regulation.\",\n      \"evidence\": \"In vitro DNA/RNA binding assays with multiple G-quadruplex substrates in a human system\",\n      \"pmids\": [\"39029558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding specificity has not been validated in vivo (e.g., ChIP or CLIP)\",\n        \"Structural basis for G-quadruplex recognition by the armadillo repeat domain is unresolved\",\n        \"Whether G-quadruplex binding is required for the hTRF2 interaction or telomerase co-precipitation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that ARMC6 overexpression alters expression of VEGF, hTERT, c-MYC, and other genes linked to oncogenic and telomerase pathways suggested a functional output of its G-quadruplex binding, but the causal mechanism remains unresolved.\",\n      \"evidence\": \"Overexpression in human cell lines with gene expression profiling\",\n      \"pmids\": [\"39029558\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Overexpression-only system without loss-of-function validation\",\n        \"No evidence that transcriptional changes are direct (i.e., mediated through promoter G-quadruplex binding by ARMC6)\",\n        \"Endogenous expression levels and chromatin occupancy of ARMC6 are uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of ARMC6 as a METTL9 substrate for histidine methylation at HxH motifs revealed a specific post-translational modification, raising the question of how this modification regulates ARMC6 function.\",\n      \"evidence\": \"In vitro methyltransferase assay with recombinant METTL9 and ARMC6 peptides/proteins\",\n      \"pmids\": [\"40451431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo methylation of ARMC6 by METTL9 has not been demonstrated\",\n        \"Functional consequence of histidine methylation on ARMC6 G-quadruplex binding or protein interactions is unknown\",\n        \"Stoichiometry and regulation of this modification in cells are uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central open question is whether ARMC6's G-quadruplex binding activity and its telomere-associated interactions operate in the same pathway, and whether histidine methylation by METTL9 modulates these activities in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No loss-of-function studies (knockout, knockdown) characterizing ARMC6's cellular phenotype\",\n        \"No in vivo evidence linking G-quadruplex binding to transcriptional regulation or telomere maintenance\",\n        \"No structural information for ARMC6 or its nucleic acid complexes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"TRF2\", \"METTL9\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ARMC6 is an armadillo repeat-containing protein that binds G-quadruplex-forming DNA and RNA structures in vitro, with preferential affinity for RNA G-quadruplexes including the telomeric repeat-containing RNA TERRA and G-quadruplex sequences from cancer gene promoters (EGFR, VEGF, c-MYC) [PMID:39029558]. ARMC6 co-precipitates telomerase activity and interacts with the shelterin component TRF2, placing it at the interface of telomere biology [PMID:29948659]. ARMC6 is a substrate of the protein histidine methyltransferase METTL9, which generates 1-methylhistidine at HxH motifs within ARMC6, establishing it as a defined target of this post-translational modification [PMID:40451431].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"The first indication that ARMC6 participates in telomere biology came from its co-precipitation with telomerase activity and physical interaction with the shelterin protein TRF2, suggesting it operates in telomere-associated pathways.\",\n      \"evidence\": \"Co-immunoprecipitation of telomerase activity and in vitro protein–protein interaction assay with human ARMC6 and TRF2\",\n      \"pmids\": [\"29948659\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single in vitro pulldown without reciprocal validation or in-cell confirmation\",\n        \"No evidence that ARMC6 localizes to telomeres in cells\",\n        \"Functional consequence of ARMC6–TRF2 interaction undefined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of ARMC6 as a G-quadruplex recognition protein explained a potential molecular basis for its telomeric and gene-regulatory associations, showing it preferentially binds RNA over DNA G-quadruplex structures including TERRA and cancer gene promoter sequences.\",\n      \"evidence\": \"Electrophoretic mobility shift assays and biochemical binding experiments with recombinant ARMC6 and defined G-quadruplex substrates; overexpression in human cell lines with downstream gene expression analysis\",\n      \"pmids\": [\"39029558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo binding targets not mapped (e.g., no CLIP or ChIP-seq)\",\n        \"Whether G-quadruplex binding is mediated by the armadillo repeats or another domain is unresolved\",\n        \"Physiological consequences of G-quadruplex binding on gene expression or telomere maintenance not established in loss-of-function studies\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that ARMC6 is methylated at HxH motifs by METTL9 established it as a bona fide substrate of protein histidine methylation, raising the question of whether this modification regulates its G-quadruplex binding or protein interactions.\",\n      \"evidence\": \"In vitro methyltransferase assay with recombinant METTL9 and ARMC6, mass spectrometric identification of 1-methylhistidine, mutagenesis of HxH motifs\",\n      \"pmids\": [\"40451431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ARMC6 is methylated by METTL9 in cells has not been shown\",\n        \"Functional impact of histidine methylation on ARMC6 activity, stability, or binding is unknown\",\n        \"Stoichiometry of modification in vivo is undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cellular function of ARMC6 remains poorly defined: it is unclear whether its G-quadruplex binding and telomere-associated interactions reflect a single unified role or distinct activities, and no loss-of-function phenotype has been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No knockout or knockdown phenotypic data available\",\n        \"No genome-wide binding profile (ChIP-seq, CLIP) to define in vivo targets\",\n        \"Relationship between METTL9-mediated methylation and G-quadruplex/telomere functions untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"TRF2\", \"METTL9\"],\n    \"other_free_text\": []\n  }\n}\n```"}