{"gene":"SAMD4A","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2005,"finding":"Mammalian SAMD4A (hSmaug1) acts as a translational repressor of reporter transcripts carrying Smaug recognition element (SRE) motifs and forms cytoplasmic granules containing polyadenylated mRNA and RNA-binding proteins Staufen, TIAR, TIA-1, and HuR; murine Smaug1 is expressed in the central nervous system, is abundant in post-synaptic densities, and is present in synaptoneurosomal 20S particles.","method":"Overexpression in fibroblasts, in vitro translation reporter assays, immunofluorescence, biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, reporter assay plus localization, moderate mechanistic follow-up","pmids":["16221671"],"is_preprint":false},{"year":2013,"finding":"Human SAMD4A (SMAUG1) physically interacts with CUGBP1 in human myoblasts, and increased SAMD4A levels correct abnormal nuclear accumulation of CUGBP1 in DM1 patient myoblasts, reduce inactive CUGBP1-eIF2α translational complexes, and restore translation of MRG15 (a CUGBP1 downstream target), demonstrating a role for SAMD4A in regulating CUGBP1 translational activity.","method":"Co-immunoprecipitation, overexpression/knockdown in human myoblasts, translation assays, immunofluorescence","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal interaction and functional phenotypic rescue in human cells, single lab","pmids":["23637619"],"is_preprint":false},{"year":2021,"finding":"SAMD4A directly destabilizes proangiogenic mRNA transcripts (CXCL5, ENG, IL1β, ANGPT1) by binding to stem-loop structures in their 3' UTRs through its SAM domain, thereby inhibiting breast tumor angiogenesis; overexpression inhibited angiogenesis and tumor progression whereas knockdown reversed this effect.","method":"RNA-binding assay (SAM domain), mRNA stability assay, overexpression/knockdown in breast cancer cells and xenograft models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct RNA binding via SAM domain demonstrated with functional consequence, single lab","pmids":["34219323"],"is_preprint":false},{"year":2020,"finding":"The circular RNA derived from the SAMD4A locus (circSAMD4A) acts as a miR-138-5p sponge, thereby increasing EZH2 expression and promoting preadipocyte differentiation; circSAMD4A knockdown reversed HFD-induced obesity phenotypes in mice.","method":"circRNA overexpression/knockdown in vitro and in vivo (HFD mice), luciferase reporter assay for miRNA sponge activity","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional rescue in vivo plus miRNA sponge mechanism validated by reporter assay, single lab","pmids":["32292524"],"is_preprint":false}],"current_model":"SAMD4A (mammalian Smaug1) is an RNA-binding protein that uses its SAM domain to recognize SRE stem-loop structures in target mRNA 3' UTRs, repressing their translation and/or promoting their destabilization; it forms cytoplasmic mRNP granules in neurons (including post-synaptic densities), interacts with CUGBP1 to regulate its translational activity, and suppresses tumor angiogenesis by directly destabilizing proangiogenic transcripts."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that mammalian SAMD4A functions as an SRE-dependent translational repressor and forms cytoplasmic mRNP granules enriched in neuronal synapses resolved the question of whether Drosophila Smaug function is conserved in mammals.","evidence":"Overexpression in fibroblasts, in vitro translation reporter assays, immunofluorescence, and biochemical fractionation of murine brain tissue","pmids":["16221671"],"confidence":"Medium","gaps":["Endogenous mammalian mRNA targets of SAMD4A were not identified","Mechanism of mRNP granule formation and its relationship to translational repression was not dissected","No loss-of-function studies in neurons"]},{"year":2013,"claim":"Demonstrating that SAMD4A physically interacts with CUGBP1 and rescues its mislocalization and translational defects in DM1 myoblasts established SAMD4A as a modulator of CUGBP1-dependent translation with disease relevance.","evidence":"Co-immunoprecipitation, overexpression/knockdown in human myoblasts, translation assays for MRG15 target","pmids":["23637619"],"confidence":"Medium","gaps":["Whether SAMD4A directly binds CUGBP1 or acts through an RNA intermediate was not resolved","Therapeutic relevance in DM1 animal models was not tested","Whether the SAMD4A-CUGBP1 axis operates outside myoblasts is unknown"]},{"year":2021,"claim":"Showing that SAMD4A directly binds stem-loop structures in the 3' UTRs of proangiogenic mRNAs via its SAM domain and destabilizes them provided the first identification of endogenous mammalian target transcripts and linked SAMD4A to tumor angiogenesis suppression.","evidence":"RNA-binding assays with SAM domain, mRNA stability measurements, overexpression/knockdown in breast cancer cells and xenograft models","pmids":["34219323"],"confidence":"Medium","gaps":["Genome-wide identification of SAMD4A direct targets (e.g., by CLIP) has not been performed","Whether mRNA destabilization involves deadenylation machinery (as in Drosophila Smaug) is untested in mammalian cells","Structural basis of SAM domain–stem-loop recognition is unresolved"]},{"year":null,"claim":"Key unresolved questions include the full spectrum of endogenous SAMD4A mRNA targets, the molecular mechanism linking SRE binding to mRNA decay (e.g., deadenylase recruitment), the structural determinants of SAM domain–RNA recognition, and the in vivo physiological roles of SAMD4A in the nervous system.","evidence":"","pmids":[],"confidence":"High","gaps":["No transcriptome-wide target map (CLIP-seq) exists for mammalian SAMD4A","No structural model of the SAM domain bound to an SRE stem-loop","In vivo neuronal loss-of-function phenotypes have not been reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CUGBP1","STAU1","TIAR","TIA1","ELAVL1"],"other_free_text":[]},"mechanistic_narrative":"SAMD4A (mammalian Smaug1) is an RNA-binding translational repressor that recognizes Smaug recognition element (SRE) stem-loop structures in target mRNA 3' UTRs through its SAM domain, leading to translational silencing and mRNA destabilization; it forms cytoplasmic mRNP granules and is enriched in neuronal post-synaptic densities [PMID:16221671]. SAMD4A directly destabilizes proangiogenic transcripts including CXCL5, ENG, IL1β, and ANGPT1, thereby suppressing tumor angiogenesis in breast cancer [PMID:34219323]. SAMD4A also physically interacts with CUGBP1 in human myoblasts, correcting its aberrant nuclear accumulation and restoring CUGBP1-dependent translation in myotonic dystrophy type 1 (DM1) patient cells [PMID:23637619]."},"prefetch_data":{"uniprot":{"accession":"Q9UPU9","full_name":"Protein Smaug homolog 1","aliases":["Sterile alpha motif domain-containing protein 4A","SAM domain-containing protein 4A"],"length_aa":718,"mass_kda":79.4,"function":"Acts as a translational repressor of SRE-containing messengers","subcellular_location":"Cytoplasm; Cell projection, dendrite; Synapse, synaptosome","url":"https://www.uniprot.org/uniprotkb/Q9UPU9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SAMD4A","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SAMD4A","total_profiled":1310},"omim":[{"mim_id":"619231","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 4B; SAMD4B","url":"https://www.omim.org/entry/619231"},{"mim_id":"610747","title":"STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 4A; SAMD4A","url":"https://www.omim.org/entry/610747"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":78.3},{"tissue":"skeletal muscle","ntpm":88.3},{"tissue":"testis","ntpm":99.6}],"url":"https://www.proteinatlas.org/search/SAMD4A"},"hgnc":{"alias_symbol":["KIAA1053","DKFZP434H0350","Smaug","SMG","SMGA","hSmaug1"],"prev_symbol":["SAMD4"]},"alphafold":{"accession":"Q9UPU9","domains":[{"cath_id":"1.10.150.50","chopping":"318-384","consensus_level":"medium","plddt":93.9073,"start":318,"end":384},{"cath_id":"1.25.40","chopping":"59-155","consensus_level":"medium","plddt":88.3353,"start":59,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPU9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPU9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPU9-F1-predicted_aligned_error_v6.png","plddt_mean":62.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAMD4A","jax_strain_url":"https://www.jax.org/strain/search?query=SAMD4A"},"sequence":{"accession":"Q9UPU9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPU9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPU9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPU9"}},"corpus_meta":[{"pmid":"8104846","id":"PMC_8104846","title":"mRNA 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SAMD4A directly destabilizes proangiogenic transcripts including CXCL5, ENG, IL1β, and ANGPT1, thereby suppressing tumor angiogenesis in breast cancer [PMID:34219323]. SAMD4A also physically interacts with CUGBP1 in human myoblasts, correcting its aberrant nuclear accumulation and restoring CUGBP1-dependent translation in myotonic dystrophy type 1 (DM1) patient cells [PMID:23637619].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that mammalian SAMD4A functions as an SRE-dependent translational repressor and forms cytoplasmic mRNP granules enriched in neuronal synapses resolved the question of whether Drosophila Smaug function is conserved in mammals.\",\n      \"evidence\": \"Overexpression in fibroblasts, in vitro translation reporter assays, immunofluorescence, and biochemical fractionation of murine brain tissue\",\n      \"pmids\": [\"16221671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous mammalian mRNA targets of SAMD4A were not identified\",\n        \"Mechanism of mRNP granule formation and its relationship to translational repression was not dissected\",\n        \"No loss-of-function studies in neurons\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that SAMD4A physically interacts with CUGBP1 and rescues its mislocalization and translational defects in DM1 myoblasts established SAMD4A as a modulator of CUGBP1-dependent translation with disease relevance.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown in human myoblasts, translation assays for MRG15 target\",\n      \"pmids\": [\"23637619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SAMD4A directly binds CUGBP1 or acts through an RNA intermediate was not resolved\",\n        \"Therapeutic relevance in DM1 animal models was not tested\",\n        \"Whether the SAMD4A-CUGBP1 axis operates outside myoblasts is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that SAMD4A directly binds stem-loop structures in the 3' UTRs of proangiogenic mRNAs via its SAM domain and destabilizes them provided the first identification of endogenous mammalian target transcripts and linked SAMD4A to tumor angiogenesis suppression.\",\n      \"evidence\": \"RNA-binding assays with SAM domain, mRNA stability measurements, overexpression/knockdown in breast cancer cells and xenograft models\",\n      \"pmids\": [\"34219323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genome-wide identification of SAMD4A direct targets (e.g., by CLIP) has not been performed\",\n        \"Whether mRNA destabilization involves deadenylation machinery (as in Drosophila Smaug) is untested in mammalian cells\",\n        \"Structural basis of SAM domain–stem-loop recognition is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full spectrum of endogenous SAMD4A mRNA targets, the molecular mechanism linking SRE binding to mRNA decay (e.g., deadenylase recruitment), the structural determinants of SAM domain–RNA recognition, and the in vivo physiological roles of SAMD4A in the nervous system.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No transcriptome-wide target map (CLIP-seq) exists for mammalian SAMD4A\",\n        \"No structural model of the SAM domain bound to an SRE stem-loop\",\n        \"In vivo neuronal loss-of-function phenotypes have not been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CUGBP1\",\n      \"STAU1\",\n      \"TIAR\",\n      \"TIA1\",\n      \"ELAVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}