{"gene":"RAMAC","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2011,"finding":"RAM (RNMT-Activating Mini protein)/Fam103a1 is an obligate component of the mammalian mRNA cap methyltransferase complex. RAM consists of an N-terminal RNMT-activating domain and a C-terminal RNA-binding domain. As monomers, RNMT and RAM have relatively weak affinity for RNA, but together their RNA affinity is significantly increased. RAM is required for efficient cap methylation both in vitro and in vivo, and is indirectly required to maintain mRNA expression levels, mRNA translation, and cell viability.","method":"Biochemical identification and characterization of the RAM-RNMT complex; in vitro cap methylation assays; RNA-binding assays; domain dissection; cell viability and translation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, domain mutagenesis, and multiple orthogonal functional assays (cap methylation, RNA binding, translation, viability) in a single rigorous study","pmids":["22099306"],"is_preprint":false},{"year":2014,"finding":"The promoter of the RAM/FAM103A1 gene is bound by Mediator head module subunit hMED18; depletion of hMED18 causes loss of hMED18 and hMED1 from the RAM/FAM103A1 promoter while CDK8 remains bound, indicating that hMED18 acts as a transcriptional repressor of RAM/FAM103A1 expression through a mechanism involving the CDK/cyclin module.","method":"siRNA-mediated depletion of hMED18; ChIP analysis of promoter occupancy by hMED18, hMED1, and hCDK8; transcriptional output measurement","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and siRNA knockdown in a single lab study establishing transcriptional regulation of RAMAC, but limited to one study with no independent replication","pmids":["24840924"],"is_preprint":false}],"current_model":"RAMAC (RAM/FAM103A1) is an obligate activating subunit of the mammalian mRNA cap methyltransferase RNMT: its N-terminal domain activates RNMT and its C-terminal domain binds RNA, and together the RAM-RNMT complex achieves the RNA affinity and cap methylation activity required for efficient gene expression, mRNA translation, and cell viability; expression of RAMAC itself is transcriptionally repressed by Mediator subunit hMED18 acting through the CDK/cyclin module."},"narrative":{"mechanistic_narrative":"RAMAC (RAM/FAM103A1) is an obligate activating subunit of the mammalian mRNA cap methyltransferase complex, where it partners with RNMT to drive efficient cap methylation required for gene expression, mRNA translation, and cell viability [PMID:22099306]. RAMAC is organized into two functional modules: an N-terminal domain that activates RNMT and a C-terminal RNA-binding domain; while RNMT and RAMAC each bind RNA only weakly as monomers, assembly into the RAM-RNMT complex markedly increases RNA affinity and confers full cap methylation activity, making RAMAC indirectly essential for maintaining mRNA levels, translation, and cell survival [PMID:22099306]. Expression of RAMAC itself is transcriptionally repressed by the Mediator head module subunit hMED18 acting through the CDK/cyclin module [PMID:24840924].","teleology":[{"year":2011,"claim":"Established that mammalian cap methylation requires not just RNMT but an obligate activating partner, answering how the enzyme achieves sufficient RNA affinity and catalytic output in cells.","evidence":"Biochemical reconstitution of the RAM-RNMT complex with in vitro cap methylation and RNA-binding assays, domain dissection, and translation/viability assays in cells","pmids":["22099306"],"confidence":"High","gaps":["Structural basis for how the N-terminal domain activates RNMT not resolved","Sequence/structural determinants of C-terminal RNA recognition not defined","Direct versus indirect contribution to specific mRNA targets not dissected"]},{"year":2014,"claim":"Addressed how RAMAC abundance is controlled by showing its promoter is repressed by a Mediator subunit, linking cap-methylation capacity to transcriptional regulation.","evidence":"siRNA depletion of hMED18 with ChIP of promoter occupancy by hMED18, hMED1, and CDK8 and transcriptional output measurement","pmids":["24840924"],"confidence":"Medium","gaps":["Single-lab ChIP/knockdown study without independent replication","Mechanism by which the CDK/cyclin module enforces repression not detailed","Physiological conditions that modulate this repression unknown"]},{"year":null,"claim":"How RAMAC-dependent cap methylation is dynamically regulated and whether it acts selectively on specific transcript classes remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the RAM-RNMT-RNA complex in the corpus","No data on transcript selectivity of RAMAC-dependent methylation","No characterization of post-translational regulation of RAMAC"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["RAM-RNMT mRNA cap methyltransferase complex"],"partners":["RNMT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BTL3","full_name":"RNA guanine-N7 methyltransferase activating subunit","aliases":["Protein FAM103A1","RNA guanine-7 methyltransferase activating subunit","RNMT-activating mRNA cap methyltransferase subunit","RNMT-activating mini protein","RAM"],"length_aa":118,"mass_kda":14.4,"function":"Regulatory subunit of the mRNA-capping methyltransferase RNMT:RAMAC complex that methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs (PubMed:22099306, PubMed:27422871). Promotes the recruitment of the methyl donor, S-adenosyl-L-methionine, to RNMT (PubMed:27422871). Regulates RNMT expression by a post-transcriptional stabilizing mechanism (PubMed:22099306). Binds RNA (PubMed:22099306)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BTL3/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAMAC"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KPNA6","stoichiometry":10.0},{"gene":"KPNA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAMAC","total_profiled":1310},"omim":[],"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/RAMAC"},"hgnc":{"alias_symbol":["HsT19360","C15orf18","MGC2560","RAM"],"prev_symbol":["FAM103A1","RAMMET"]},"alphafold":{"accession":"Q9BTL3","domains":[{"cath_id":"-","chopping":"3-32","consensus_level":"high","plddt":91.9293,"start":3,"end":32}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTL3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTL3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTL3-F1-predicted_aligned_error_v6.png","plddt_mean":62.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAMAC","jax_strain_url":"https://www.jax.org/strain/search?query=RAMAC"},"sequence":{"accession":"Q9BTL3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BTL3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BTL3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTL3"}},"corpus_meta":[{"pmid":"22099306","id":"PMC_22099306","title":"RAM/Fam103a1 is required for mRNA cap methylation.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22099306","citation_count":88,"is_preprint":false},{"pmid":"34680890","id":"PMC_34680890","title":"Genome-Wide Association Studies for Milk Somatic Cell Score in Romanian Dairy Cattle.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34680890","citation_count":18,"is_preprint":false},{"pmid":"24840924","id":"PMC_24840924","title":"Mediator MED18 subunit plays a negative role in transcription via the CDK/cyclin module.","date":"2014","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/24840924","citation_count":7,"is_preprint":false},{"pmid":"38302055","id":"PMC_38302055","title":"Proliferative Sickle Cell Retinopathy: Outcomes of Vitreoretinal Surgery.","date":"2024","source":"Ophthalmology. Retina","url":"https://pubmed.ncbi.nlm.nih.gov/38302055","citation_count":7,"is_preprint":false},{"pmid":"34003694","id":"PMC_34003694","title":"Screening of Potential Key Genes Related to Tubal Factor Infertility Based on Competitive Endogenous RNA Network.","date":"2021","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/34003694","citation_count":5,"is_preprint":false},{"pmid":"32894148","id":"PMC_32894148","title":"A 15q25.2 microdeletion phenotype for premature ovarian failure in a Chinese girl: a case report and review of literature.","date":"2020","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32894148","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5621,"output_tokens":739,"usd":0.013974,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7128,"output_tokens":1246,"usd":0.033395,"stage2_stop_reason":"end_turn"},"total_usd":0.047369,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"RAM (RNMT-Activating Mini protein)/Fam103a1 is an obligate component of the mammalian mRNA cap methyltransferase complex. RAM consists of an N-terminal RNMT-activating domain and a C-terminal RNA-binding domain. As monomers, RNMT and RAM have relatively weak affinity for RNA, but together their RNA affinity is significantly increased. RAM is required for efficient cap methylation both in vitro and in vivo, and is indirectly required to maintain mRNA expression levels, mRNA translation, and cell viability.\",\n      \"method\": \"Biochemical identification and characterization of the RAM-RNMT complex; in vitro cap methylation assays; RNA-binding assays; domain dissection; cell viability and translation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, domain mutagenesis, and multiple orthogonal functional assays (cap methylation, RNA binding, translation, viability) in a single rigorous study\",\n      \"pmids\": [\"22099306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The promoter of the RAM/FAM103A1 gene is bound by Mediator head module subunit hMED18; depletion of hMED18 causes loss of hMED18 and hMED1 from the RAM/FAM103A1 promoter while CDK8 remains bound, indicating that hMED18 acts as a transcriptional repressor of RAM/FAM103A1 expression through a mechanism involving the CDK/cyclin module.\",\n      \"method\": \"siRNA-mediated depletion of hMED18; ChIP analysis of promoter occupancy by hMED18, hMED1, and hCDK8; transcriptional output measurement\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and siRNA knockdown in a single lab study establishing transcriptional regulation of RAMAC, but limited to one study with no independent replication\",\n      \"pmids\": [\"24840924\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAMAC (RAM/FAM103A1) is an obligate activating subunit of the mammalian mRNA cap methyltransferase RNMT: its N-terminal domain activates RNMT and its C-terminal domain binds RNA, and together the RAM-RNMT complex achieves the RNA affinity and cap methylation activity required for efficient gene expression, mRNA translation, and cell viability; expression of RAMAC itself is transcriptionally repressed by Mediator subunit hMED18 acting through the CDK/cyclin module.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAMAC (RAM/FAM103A1) is an obligate activating subunit of the mammalian mRNA cap methyltransferase complex, where it partners with RNMT to drive efficient cap methylation required for gene expression, mRNA translation, and cell viability [#0]. RAMAC is organized into two functional modules: an N-terminal domain that activates RNMT and a C-terminal RNA-binding domain; while RNMT and RAMAC each bind RNA only weakly as monomers, assembly into the RAM-RNMT complex markedly increases RNA affinity and confers full cap methylation activity, making RAMAC indirectly essential for maintaining mRNA levels, translation, and cell survival [#0]. Expression of RAMAC itself is transcriptionally repressed by the Mediator head module subunit hMED18 acting through the CDK/cyclin module [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that mammalian cap methylation requires not just RNMT but an obligate activating partner, answering how the enzyme achieves sufficient RNA affinity and catalytic output in cells.\",\n      \"evidence\": \"Biochemical reconstitution of the RAM-RNMT complex with in vitro cap methylation and RNA-binding assays, domain dissection, and translation/viability assays in cells\",\n      \"pmids\": [\"22099306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how the N-terminal domain activates RNMT not resolved\",\n        \"Sequence/structural determinants of C-terminal RNA recognition not defined\",\n        \"Direct versus indirect contribution to specific mRNA targets not dissected\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Addressed how RAMAC abundance is controlled by showing its promoter is repressed by a Mediator subunit, linking cap-methylation capacity to transcriptional regulation.\",\n      \"evidence\": \"siRNA depletion of hMED18 with ChIP of promoter occupancy by hMED18, hMED1, and CDK8 and transcriptional output measurement\",\n      \"pmids\": [\"24840924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab ChIP/knockdown study without independent replication\",\n        \"Mechanism by which the CDK/cyclin module enforces repression not detailed\",\n        \"Physiological conditions that modulate this repression unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAMAC-dependent cap methylation is dynamically regulated and whether it acts selectively on specific transcript classes remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the RAM-RNMT-RNA complex in the corpus\",\n        \"No data on transcript selectivity of RAMAC-dependent methylation\",\n        \"No characterization of post-translational regulation of RAMAC\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"RAM-RNMT mRNA cap methyltransferase complex\"],\n    \"partners\": [\"RNMT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}