{"gene":"TENT4A","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"TENT4A (PAPD7) and TENT4B (PAPD5) are the enzymes responsible for mRNA guanylation, generating a mixed poly(A) tail with intermittent non-adenosine residues (most commonly guanosine). A single guanosine residue is sufficient to impede the CCR4-NOT deadenylase complex, shielding mRNA from rapid deadenylation. Depletion of TENT4A and TENT4B leads to decreased mRNA half-life and abundance.","method":"Purified protein in vitro assay, tail-seq, siRNA knockdown, CCR4-NOT deadenylation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — purified protein biochemistry, multiple orthogonal methods (in vitro assay, sequencing, KD phenotype), single rigorous study with strong mechanistic resolution","pmids":["30026317"],"is_preprint":false},{"year":2021,"finding":"TENT4A (PAPD7) regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase by controlling their poly(A) tail lengths, thereby regulating translesion DNA synthesis (TLS). TENT4A also indirectly regulates RAD18 via the tumor suppressor CYLD and via the lncRNA PAXIP1-AS2. Knockdown of TENT4A reduces RAD18 protein levels, PCNA monoubiquitination, and TLS.","method":"siRNA knockdown, poly(A) tail length analysis, TLS assay, western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — single lab, multiple orthogonal methods (KD, tail analysis, TLS assay) but no in vitro reconstitution","pmids":["34203408"],"is_preprint":false},{"year":2013,"finding":"A novel long isoform of PAPD7 (PAPD7-l) contains 230 extra amino acids at the N-terminus compared to the short isoform (PAPD7-s). Unlike the inactive short isoform, PAPD7-l exhibits robust nucleotidyl transferase activity when tethered to RNA. A region at residues 187–219 is required for both activity and nuclear retention. Western blot confirmed PAPD7-l is the major active isoform expressed in HeLa and U2OS cells.","method":"In vitro nucleotidyl transferase assay, deletion mutagenesis, siRNA knockdown, western blot, subcellular fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with mutagenesis, single lab","pmids":["23376078"],"is_preprint":false},{"year":2020,"finding":"PAPD5 and PAPD7 (TENT4A) physically associate with HBV RNA and their polyadenylating activities are required for HBV mRNA stabilization. Inhibition by RG7834 or double knockout of PAPD5/7 leads to poly(A) tail shortening and accelerated HBV mRNA degradation. PAPD7 serves as a second layer of protection for HBV RNA integrity after PAPD5.","method":"RNA immunoprecipitation, in vitro polyadenylation assay, small-molecule inhibition (RG7834), CRISPR knockout, poly(A) tail length analysis","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical assay plus genetic KO, single lab, replicated across two studies","pmids":["33046485"],"is_preprint":false},{"year":2021,"finding":"PAPD5 plays a dominant role in maintaining HBV poly(A) tail integrity (PAPD5 KO impairs poly(A) tail integrity), while PAPD7 (TENT4A) serves as a secondary protective layer (PAPD7 KO alone does not reduce HBsAg RNA, but double PAPD5/PAPD7 KO reduces HBsAg production). The stem-loop alpha in the viral PRE is essential for sensitivity to PAPD5/7 inhibition.","method":"CRISPR knockout (single and double), small-molecule inhibitor (AB-452), HBV infection model, poly(A) tail analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypic readout, single lab, multiple orthogonal approaches","pmids":["34191584"],"is_preprint":false},{"year":2011,"finding":"The human TENT4A orthologue PAPD7 interacts with hZCCHC7 (the putative human Air1 orthologue) in a manner analogous to yeast TRAMP. This interaction suggests a conserved human TRAMP-like complex containing PAPD7 and hZCCHC7.","method":"Co-immunoprecipitation, localization assay","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, no functional reconstitution of human complex","pmids":["21878619"],"is_preprint":false},{"year":2025,"finding":"TENT4A/4B polymerases promote oligoadenylation of nascent unstable small non-coding RNAs (sncRNAs), particularly incompletely processed snoRNAs, directing them toward degradation rather than maturation.","method":"Genome-wide 3' end sequencing of nascent and steady-state sncRNAs; TENT4A/4B perturbation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide sequencing with genetic perturbation, preprint, single lab","pmids":["bio_10.1101_2025.01.31.635978"],"is_preprint":true}],"current_model":"TENT4A (PAPD7) is a non-canonical poly(A) polymerase that generates mixed poly(A) tails on mRNAs by incorporating non-adenosine residues (predominantly guanosine), which impedes the CCR4-NOT deadenylase complex and thereby stabilizes mRNA; it also oligoadenylates unstable non-coding RNAs to target them for nuclear exosome degradation, stabilizes HBV viral RNA as a secondary layer after PAPD5, and regulates translesion DNA synthesis by controlling poly(A) tail lengths of RAD18 and DNA polymerase η mRNAs."},"narrative":{"mechanistic_narrative":"TENT4A (PAPD7) is a non-canonical poly(A) polymerase that controls RNA fate by adding non-adenosine residues to RNA 3' ends, acting in two opposing directions depending on substrate. Together with TENT4B (PAPD5), it generates mixed poly(A) tails on mRNAs in which intermittent guanosine residues are incorporated; a single guanosine is sufficient to impede the CCR4-NOT deadenylase, and loss of TENT4A/4B shortens tails and reduces mRNA half-life and abundance [PMID:30026317]. The enzymatic activity resides in a long isoform (PAPD7-l) bearing an N-terminal extension whose residues 187–219 are required for both nucleotidyl transferase activity and nuclear retention, with the short isoform being inactive [PMID:23376078]. Through this tail-length control, TENT4A governs mRNAs encoding RAD18 and DNA polymerase η to promote PCNA monoubiquitination and translesion DNA synthesis [PMID:34203408]. TENT4A also stabilizes HBV viral RNA, serving as a secondary protective layer after PAPD5 via a stem-loop in the viral post-transcriptional regulatory element [PMID:33046485, PMID:34191584]. Beyond mRNA stabilization, the enzyme oligoadenylates nascent unstable small non-coding RNAs to direct them toward degradation [PMID:bio_10.1101_2025.01.31.635978].","teleology":[{"year":2011,"claim":"Whether human PAPD7 participates in a TRAMP-like RNA surveillance complex was unknown; identifying a partner placed it in a nuclear RNA-processing context.","evidence":"Co-immunoprecipitation and localization assay showing PAPD7 interacts with hZCCHC7 analogous to yeast TRAMP","pmids":["21878619"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or reconstitution of the human complex","No functional readout linking the interaction to RNA degradation"]},{"year":2013,"claim":"It was unclear which PAPD7 form is catalytically competent; isoform characterization revealed that an N-terminally extended long isoform carries the enzymatic activity.","evidence":"In vitro nucleotidyl transferase assay with deletion mutagenesis, knockdown, and subcellular fractionation in HeLa and U2OS cells","pmids":["23376078"],"confidence":"Medium","gaps":["Physiological RNA substrates of the active isoform not defined here","Mechanism by which residues 187–219 confer nuclear retention unresolved"]},{"year":2018,"claim":"The molecular basis for how non-canonical polymerases stabilize mRNA was unknown; this established that TENT4A/4B incorporate guanosine into mixed poly(A) tails to block CCR4-NOT deadenylation.","evidence":"Purified protein in vitro assays, tail-seq, siRNA knockdown, and CCR4-NOT deadenylation assays","pmids":["30026317"],"confidence":"High","gaps":["Relative contributions of TENT4A vs TENT4B to specific transcripts not separated","Determinants of which mRNAs are guanylated unknown"]},{"year":2020,"claim":"Whether TENT4A contributes to viral RNA persistence was unknown; it was shown to bind HBV RNA and protect it via polyadenylation as a backup to PAPD5.","evidence":"RNA immunoprecipitation, in vitro polyadenylation, RG7834 inhibition, CRISPR knockout, and poly(A) tail analysis","pmids":["33046485"],"confidence":"Medium","gaps":["Direct in vitro reconstitution of HBV RNA tailing by PAPD7 alone not shown","Quantitative hierarchy between PAPD5 and PAPD7 not fully resolved"]},{"year":2021,"claim":"The functional consequence of TENT4A tail control on cellular pathways was unknown; it was linked to translesion DNA synthesis through tail-length control of RAD18 and DNA polymerase η mRNAs.","evidence":"siRNA knockdown, poly(A) tail length analysis, TLS assay, and western blot","pmids":["34203408"],"confidence":"Medium","gaps":["No in vitro reconstitution of TENT4A acting on these mRNAs","Direct vs indirect (CYLD, PAXIP1-AS2) routes not fully disentangled"]},{"year":2021,"claim":"The division of labor in HBV RNA protection was refined, establishing PAPD5 as dominant and PAPD7 as a secondary layer dependent on the viral PRE stem-loop alpha.","evidence":"Single and double CRISPR knockouts, AB-452 inhibitor, HBV infection model, and poly(A) tail analysis","pmids":["34191584"],"confidence":"Medium","gaps":["Structural basis of stem-loop alpha recognition unknown","Single-lab evidence for the secondary-layer model"]},{"year":2025,"claim":"Whether TENT4A also acts destructively on RNA was unclear; it was shown to oligoadenylate unstable small non-coding RNAs to route them toward degradation.","evidence":"Genome-wide 3' end sequencing of nascent and steady-state sncRNAs with TENT4A/4B perturbation (preprint)","pmids":["bio_10.1101_2025.01.31.635978"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Connection to a nuclear exosome targeting complex not demonstrated biochemically"]},{"year":null,"claim":"How TENT4A selects between a stabilizing (guanylating) versus destabilizing (oligoadenylating) outcome on different RNA substrates remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or nucleotide selection","Recruitment determinants distinguishing mRNA from sncRNA substrates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]}],"complexes":["TRAMP-like complex (PAPD7–hZCCHC7)"],"partners":["TENT4B","ZCCHC7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5XG87","full_name":"Terminal nucleotidyltransferase 4A","aliases":["DNA polymerase sigma","LAK-1","Non-canonical poly(A) RNA polymerase PAPD7","PAP-associated domain-containing protein 7","TRAMP-like complex polyadenylate polymerase","Terminal guanylyltransferase","Terminal uridylyltransferase 5","TUTase 5","Topoisomerase-related function protein 4-1","TRF4-1"],"length_aa":792,"mass_kda":84.7,"function":"Terminal nucleotidyltransferase that catalyzes preferentially the transfer of ATP and GTP on RNA 3' poly(A) tail creating a heterogeneous 3' poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation (PubMed:23376078, PubMed:30026317). Also functions as a catalytic subunit of a TRAMP-like complex which has a poly(A) RNA polymerase activity and is involved in a post-transcriptional quality control mechanism. Polyadenylation with short oligo(A) tails is required for the degradative activity of the exosome on several of its nuclear RNA substrates. Has no terminal uridylyltransferase activity, and does not play a role in replication-dependent histone mRNA degradation via uridylation (PubMed:23376078)","subcellular_location":"Cytoplasm; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q5XG87/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TENT4A","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TENT4A","total_profiled":1310},"omim":[{"mim_id":"620697","title":"ZINC FINGER CCHC DOMAIN-CONTAINING PROTEIN 14; ZCCHC14","url":"https://www.omim.org/entry/620697"},{"mim_id":"605540","title":"TERMINAL NUCLEOTIDYLTRANSFERASE 4B; TENT4B","url":"https://www.omim.org/entry/605540"},{"mim_id":"605198","title":"TERMINAL NUCLEOTIDYLTRANSFERASE 4A; TENT4A","url":"https://www.omim.org/entry/605198"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TENT4A"},"hgnc":{"alias_symbol":["POLK","TRF4","LAK-1","TRF4-1"],"prev_symbol":["POLS","PAPD7"]},"alphafold":{"accession":"Q5XG87","domains":[{"cath_id":"1.10.1410.10","chopping":"206-233_355-531","consensus_level":"medium","plddt":91.2,"start":206,"end":531},{"cath_id":"3.30.460.10","chopping":"235-270_272-339","consensus_level":"medium","plddt":94.3652,"start":235,"end":339}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XG87","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XG87-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XG87-F1-predicted_aligned_error_v6.png","plddt_mean":60.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TENT4A","jax_strain_url":"https://www.jax.org/strain/search?query=TENT4A"},"sequence":{"accession":"Q5XG87","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5XG87.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5XG87/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XG87"}},"corpus_meta":[{"pmid":"18007593","id":"PMC_18007593","title":"Trf4 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A single guanosine residue is sufficient to impede the CCR4-NOT deadenylase complex, shielding mRNA from rapid deadenylation. Depletion of TENT4A and TENT4B leads to decreased mRNA half-life and abundance.\",\n      \"method\": \"Purified protein in vitro assay, tail-seq, siRNA knockdown, CCR4-NOT deadenylation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — purified protein biochemistry, multiple orthogonal methods (in vitro assay, sequencing, KD phenotype), single rigorous study with strong mechanistic resolution\",\n      \"pmids\": [\"30026317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TENT4A (PAPD7) regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase by controlling their poly(A) tail lengths, thereby regulating translesion DNA synthesis (TLS). TENT4A also indirectly regulates RAD18 via the tumor suppressor CYLD and via the lncRNA PAXIP1-AS2. Knockdown of TENT4A reduces RAD18 protein levels, PCNA monoubiquitination, and TLS.\",\n      \"method\": \"siRNA knockdown, poly(A) tail length analysis, TLS assay, western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — single lab, multiple orthogonal methods (KD, tail analysis, TLS assay) but no in vitro reconstitution\",\n      \"pmids\": [\"34203408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel long isoform of PAPD7 (PAPD7-l) contains 230 extra amino acids at the N-terminus compared to the short isoform (PAPD7-s). Unlike the inactive short isoform, PAPD7-l exhibits robust nucleotidyl transferase activity when tethered to RNA. A region at residues 187–219 is required for both activity and nuclear retention. Western blot confirmed PAPD7-l is the major active isoform expressed in HeLa and U2OS cells.\",\n      \"method\": \"In vitro nucleotidyl transferase assay, deletion mutagenesis, siRNA knockdown, western blot, subcellular fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with mutagenesis, single lab\",\n      \"pmids\": [\"23376078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PAPD5 and PAPD7 (TENT4A) physically associate with HBV RNA and their polyadenylating activities are required for HBV mRNA stabilization. Inhibition by RG7834 or double knockout of PAPD5/7 leads to poly(A) tail shortening and accelerated HBV mRNA degradation. PAPD7 serves as a second layer of protection for HBV RNA integrity after PAPD5.\",\n      \"method\": \"RNA immunoprecipitation, in vitro polyadenylation assay, small-molecule inhibition (RG7834), CRISPR knockout, poly(A) tail length analysis\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical assay plus genetic KO, single lab, replicated across two studies\",\n      \"pmids\": [\"33046485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAPD5 plays a dominant role in maintaining HBV poly(A) tail integrity (PAPD5 KO impairs poly(A) tail integrity), while PAPD7 (TENT4A) serves as a secondary protective layer (PAPD7 KO alone does not reduce HBsAg RNA, but double PAPD5/PAPD7 KO reduces HBsAg production). The stem-loop alpha in the viral PRE is essential for sensitivity to PAPD5/7 inhibition.\",\n      \"method\": \"CRISPR knockout (single and double), small-molecule inhibitor (AB-452), HBV infection model, poly(A) tail analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypic readout, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"34191584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The human TENT4A orthologue PAPD7 interacts with hZCCHC7 (the putative human Air1 orthologue) in a manner analogous to yeast TRAMP. This interaction suggests a conserved human TRAMP-like complex containing PAPD7 and hZCCHC7.\",\n      \"method\": \"Co-immunoprecipitation, localization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, no functional reconstitution of human complex\",\n      \"pmids\": [\"21878619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TENT4A/4B polymerases promote oligoadenylation of nascent unstable small non-coding RNAs (sncRNAs), particularly incompletely processed snoRNAs, directing them toward degradation rather than maturation.\",\n      \"method\": \"Genome-wide 3' end sequencing of nascent and steady-state sncRNAs; TENT4A/4B perturbation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide sequencing with genetic perturbation, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.31.635978\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TENT4A (PAPD7) is a non-canonical poly(A) polymerase that generates mixed poly(A) tails on mRNAs by incorporating non-adenosine residues (predominantly guanosine), which impedes the CCR4-NOT deadenylase complex and thereby stabilizes mRNA; it also oligoadenylates unstable non-coding RNAs to target them for nuclear exosome degradation, stabilizes HBV viral RNA as a secondary layer after PAPD5, and regulates translesion DNA synthesis by controlling poly(A) tail lengths of RAD18 and DNA polymerase η mRNAs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TENT4A (PAPD7) is a non-canonical poly(A) polymerase that controls RNA fate by adding non-adenosine residues to RNA 3' ends, acting in two opposing directions depending on substrate. Together with TENT4B (PAPD5), it generates mixed poly(A) tails on mRNAs in which intermittent guanosine residues are incorporated; a single guanosine is sufficient to impede the CCR4-NOT deadenylase, and loss of TENT4A/4B shortens tails and reduces mRNA half-life and abundance [#0]. The enzymatic activity resides in a long isoform (PAPD7-l) bearing an N-terminal extension whose residues 187–219 are required for both nucleotidyl transferase activity and nuclear retention, with the short isoform being inactive [#2]. Through this tail-length control, TENT4A governs mRNAs encoding RAD18 and DNA polymerase η to promote PCNA monoubiquitination and translesion DNA synthesis [#1]. TENT4A also stabilizes HBV viral RNA, serving as a secondary protective layer after PAPD5 via a stem-loop in the viral post-transcriptional regulatory element [#3, #4]. Beyond mRNA stabilization, the enzyme oligoadenylates nascent unstable small non-coding RNAs to direct them toward degradation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether human PAPD7 participates in a TRAMP-like RNA surveillance complex was unknown; identifying a partner placed it in a nuclear RNA-processing context.\",\n      \"evidence\": \"Co-immunoprecipitation and localization assay showing PAPD7 interacts with hZCCHC7 analogous to yeast TRAMP\",\n      \"pmids\": [\"21878619\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or reconstitution of the human complex\", \"No functional readout linking the interaction to RNA degradation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"It was unclear which PAPD7 form is catalytically competent; isoform characterization revealed that an N-terminally extended long isoform carries the enzymatic activity.\",\n      \"evidence\": \"In vitro nucleotidyl transferase assay with deletion mutagenesis, knockdown, and subcellular fractionation in HeLa and U2OS cells\",\n      \"pmids\": [\"23376078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological RNA substrates of the active isoform not defined here\", \"Mechanism by which residues 187–219 confer nuclear retention unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The molecular basis for how non-canonical polymerases stabilize mRNA was unknown; this established that TENT4A/4B incorporate guanosine into mixed poly(A) tails to block CCR4-NOT deadenylation.\",\n      \"evidence\": \"Purified protein in vitro assays, tail-seq, siRNA knockdown, and CCR4-NOT deadenylation assays\",\n      \"pmids\": [\"30026317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of TENT4A vs TENT4B to specific transcripts not separated\", \"Determinants of which mRNAs are guanylated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether TENT4A contributes to viral RNA persistence was unknown; it was shown to bind HBV RNA and protect it via polyadenylation as a backup to PAPD5.\",\n      \"evidence\": \"RNA immunoprecipitation, in vitro polyadenylation, RG7834 inhibition, CRISPR knockout, and poly(A) tail analysis\",\n      \"pmids\": [\"33046485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro reconstitution of HBV RNA tailing by PAPD7 alone not shown\", \"Quantitative hierarchy between PAPD5 and PAPD7 not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The functional consequence of TENT4A tail control on cellular pathways was unknown; it was linked to translesion DNA synthesis through tail-length control of RAD18 and DNA polymerase η mRNAs.\",\n      \"evidence\": \"siRNA knockdown, poly(A) tail length analysis, TLS assay, and western blot\",\n      \"pmids\": [\"34203408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of TENT4A acting on these mRNAs\", \"Direct vs indirect (CYLD, PAXIP1-AS2) routes not fully disentangled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The division of labor in HBV RNA protection was refined, establishing PAPD5 as dominant and PAPD7 as a secondary layer dependent on the viral PRE stem-loop alpha.\",\n      \"evidence\": \"Single and double CRISPR knockouts, AB-452 inhibitor, HBV infection model, and poly(A) tail analysis\",\n      \"pmids\": [\"34191584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of stem-loop alpha recognition unknown\", \"Single-lab evidence for the secondary-layer model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether TENT4A also acts destructively on RNA was unclear; it was shown to oligoadenylate unstable small non-coding RNAs to route them toward degradation.\",\n      \"evidence\": \"Genome-wide 3' end sequencing of nascent and steady-state sncRNAs with TENT4A/4B perturbation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.31.635978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Connection to a nuclear exosome targeting complex not demonstrated biochemically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TENT4A selects between a stabilizing (guanylating) versus destabilizing (oligoadenylating) outcome on different RNA substrates remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or nucleotide selection\", \"Recruitment determinants distinguishing mRNA from sncRNA substrates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"TRAMP-like complex (PAPD7–hZCCHC7)\"],\n    \"partners\": [\"TENT4B\", \"ZCCHC7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}