{"gene":"TENT4B","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"TENT4B (PAPD5) and TENT4A (PAPD7) are the enzymes responsible for mRNA guanylation; purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues (most commonly guanosine). A single guanosine residue in the tail is sufficient to impede the CCR4-NOT deadenylase complex, shielding mRNA from rapid deadenylation. Depletion of both TENT4A and TENT4B decreases mRNA half-life and abundance in cells.","method":"Biochemical purification of recombinant proteins, in vitro tail-synthesis assay, deadenylation assay with CCR4-NOT, siRNA knockdown with mRNA half-life measurement","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted enzymatic activity in vitro with purified proteins, mechanistic mutagenesis-equivalent single-G insertion assay, and cellular loss-of-function with defined phenotype, single rigorous study with multiple orthogonal methods","pmids":["30026317"],"is_preprint":false},{"year":2011,"finding":"Recombinant PAPD5 catalyzes polyadenylation of diverse RNA substrates in vitro as a single polypeptide without a protein cofactor, in contrast to its yeast homolog Trf4p which requires a separate RNA-binding subunit. The C-terminal basic amino acid stretch of PAPD5 is involved in binding the RNA substrate.","method":"In vitro polyadenylation assay with recombinant PAPD5 expressed in mammalian cells and bacteria; deletion/domain analysis of C-terminal basic region","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with domain mutagenesis, single lab but multiple substrate conditions","pmids":["21788334"],"is_preprint":false},{"year":2012,"finding":"PAPD5 is responsible for adding oligo(A) tails to processing intermediates of H/ACA box snoRNAs (and scaRNAs) in human cells; these oligoadenylated intermediates are subsequently trimmed by PARN. Knockdown of PAPD5 abolishes accumulation of oligoadenylated snoRNA stubs. PARN is concentrated in nucleoli and Cajal bodies consistent with this role.","method":"siRNA knockdown of PAPD5 and PARN in human cells; Northern blotting and sequencing of snoRNA 3'-end intermediates; subcellular fractionation/immunofluorescence of PARN","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdown of writer (PAPD5) and eraser (PARN) with direct sequencing of modified RNA ends, two orthogonal methods, single lab","pmids":["22442037"],"is_preprint":false},{"year":2014,"finding":"PAPD5 adenylates the 3' end of mature miR-21 in human cells; PAPD5 knockdown causes increased miR-21 levels, while PARN degrades adenylated miR-21 in the 3'-to-5' direction. This tailing-and-trimming pathway results in down-regulation of miR-21 target mRNAs.","method":"siRNA knockdown of PAPD5 and exoribonucleases; small-RNA sequencing to detect adenylated miR-21 isomiRs; microarray profiling of target mRNA expression changes","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus small-RNA sequencing showing adenylated isomiRs, functional readout via target mRNA microarray, single lab","pmids":["25049417"],"is_preprint":false},{"year":2019,"finding":"PAPD5 (and PAPD7) oligoadenylates the telomerase RNA component TERC, destabilizing it. Knockdown or inhibition of PAPD5 in DKC1-mutant cells partially restores TERC levels and telomerase activity. The PAPD5–EXOSC10 axis mediates TERC degradation downstream of oligoadenylation.","method":"RNAi knockdown of PAPD5 in hESCs with DKC1_A353V mutation; measurement of TERC levels, telomerase activity, and telomere length; genetic silencing of PAPD5 as rescue experiment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (PAPD5 silencing) in disease-relevant hESC model with multiple functional readouts (TERC levels, telomerase activity, telomere elongation), replicated across two independent groups (PMIDs 30728146, 32559291, 32320679)","pmids":["30728146","32559291","32320679"],"is_preprint":false},{"year":2019,"finding":"PAPD5 and PAPD7 are identified as the cellular protein targets of the HBV inhibitor RG7834 via yeast three-hybrid screen; the drug interaction was mapped to the catalytic domains of both enzymes. PAPD5 and PAPD7 are required for HBV RNA stabilization: knockdown phenocopies RG7834 treatment by destabilizing HBV mRNA without affecting transcription, and simultaneous knockdown of both shows the greatest effect, indicating functional redundancy.","method":"Compound-based yeast three-hybrid screen; domain-mapping of RG7834 binding to catalytic domain; siRNA knockdown of PAPD5/7 in HBV-infected hepatocytes; HBV mRNA stability assay","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — target identification by protein-interaction screen plus domain mapping plus genetic knockdown phenocopy, replicated across multiple labs (PMIDs 30365161, 33046485, 34191584)","pmids":["30365161","33046485","34191584"],"is_preprint":false},{"year":2020,"finding":"In HBV-expressing cells, PAPD5 and PAPD7 are physically associated with viral RNA. Inhibition of their polyadenylating activities by RG7834 leads to poly(A) tail shortening of HBV mRNA followed by accelerated nuclear and cytoplasmic degradation. In PAPD5/7 double-knockout cells, viral transcripts with normal poly(A) length can initially be synthesized but become shortened within hours.","method":"RNA co-immunoprecipitation (PAPD5/7 with HBV RNA); biochemical polyadenylation assay susceptibility to RG7834; poly(A) tail length analysis; PAPD5/7 double-knockout cell lines","journal":"Antimicrobial Agents and Chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA co-IP plus biochemical inhibition assay plus genetic knockout, single lab","pmids":["33046485"],"is_preprint":false},{"year":2021,"finding":"PAPD5 plays a dominant role in stabilizing HBV RNA by protecting the integrity of its poly(A) tail (PAPD5 KO impairs poly(A) tail integrity); PAPD7 serves as a second line of protection without measurable poly(A) tail effects alone. The stem-loop alpha sequence within the viral PRE is essential for maintaining poly(A) tail integrity and for sensitivity to PAPD5/7 inhibitors. Both PAPD5 and PAPD7 double-KO is required to reduce HBsAg production.","method":"Individual and double CRISPR knockout of PAPD5/7; poly(A) tail length sequencing; site-directed mutagenesis of viral PRE stem-loop alpha; inhibitor resistance assays","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with poly(A) tail sequencing and cis-element mutagenesis, single lab","pmids":["34191584"],"is_preprint":false},{"year":2016,"finding":"miR-4728-3p (encoded in the HER2 intron) stabilizes miR-21-5p by inhibiting PAPD5, establishing that PAPD5-mediated 3' adenylation of miR-21-5p promotes its degradation in a PARN-dependent manner.","method":"miRNA transfection and inhibition experiments; PAPD5 expression and activity measurement after miR-4728-3p manipulation; miR-21-5p abundance assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — indirect regulation via miRNA inhibition of PAPD5 with downstream miR-21 abundance measurement, builds on prior PAPD5-miR-21 mechanism, single lab","pmids":["27752128"],"is_preprint":false},{"year":2025,"finding":"In Huntington's disease models, the transcriptional repressor YY1 is sequestered to RNA foci and protein aggregates, leading to derepression and upregulation of PAPD5. Elevated PAPD5 increases adenylation of a subset of miRNAs (including miR-7-5p), reducing their levels, which activates the TAB2-TAK1-MKK4-JNK pro-apoptotic pathway and causes neuronal death. A small-molecule PAPD5 inhibitor (BCH001) mitigates this cell death.","method":"HD cell and iPSC-derived neuron models; PAPD5 expression and miRNA adenylation profiling; YY1 localization studies; TAK1-MKK4-JNK pathway activation assays; BCH001 inhibitor rescue experiments in disease models","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (inhibitor) plus mechanistic pathway epistasis in multiple HD models including patient-derived neurons, single lab","pmids":["40204699"],"is_preprint":false},{"year":2026,"finding":"Recombinant TENT4B can perform primer- and template-independent de novo RNA polymerization from free NTPs, consuming ATP to yield inorganic pyrophosphate and oligomeric poly-adenosine RNA products. The de novo synthesis efficiency is similar whether or not a primer is included. Guanosine nucleotide polymerization is self-limited and yields a 3'-exonuclease-resistant oligonucleotide. Nucleotide diphosphates can also serve as substrates.","method":"In vitro biochemical assay with recombinant TENT4B; ATP consumption / pyrophosphate detection; 5'-radiolabeled γ-phosphate-modified NTP incorporation; primer-free RNA product sequencing; comparison across NTP types and concentrations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro reconstitution with recombinant enzyme and multiple substrate conditions, but preprint/single lab, not yet peer-reviewed","pmids":["41847027"],"is_preprint":true}],"current_model":"TENT4B (PAPD5) is a non-canonical poly(A) polymerase that adds mixed adenosine/guanosine tails to mRNAs to shield them from CCR4-NOT-mediated deadenylation, oligoadenylates H/ACA box snoRNA processing intermediates and mature miRNAs (including miR-21) to promote their PARN-dependent trimming or degradation, oligoadenylates TERC to target it for exosome-mediated degradation, stabilizes HBV RNA by protecting viral poly(A) tail integrity via physical association with viral PRE, and can also perform primer- and template-independent de novo RNA synthesis in vitro."},"narrative":{"mechanistic_narrative":"TENT4B (PAPD5) is a non-canonical poly(A) polymerase that controls RNA stability in opposite directions depending on substrate, acting as a single-polypeptide enzyme that binds RNA through its C-terminal basic region and polymerizes nucleotides without an accessory RNA-binding cofactor [PMID:21788334]. On mRNA, TENT4B (together with TENT4A) builds mixed poly(A) tails in which intermittent non-adenosine residues — most commonly guanosine — are interspersed; a single guanosine is sufficient to stall the CCR4-NOT deadenylase, so this guanylation shields transcripts from rapid deadenylation and sustains mRNA half-life and abundance [PMID:30026317]. The same adenylating activity instead marks several non-coding RNAs for turnover: TENT4B adds oligo(A) tails to H/ACA box snoRNA/scaRNA processing intermediates that are then trimmed by PARN [PMID:22442037], adenylates mature miR-21 and other miRNAs to drive their PARN-dependent degradation [PMID:25049417], and oligoadenylates the telomerase RNA TERC to route it for EXOSC10-mediated decay, such that silencing TENT4B in DKC1-mutant cells restores TERC, telomerase activity, and telomere length [PMID:30728146, PMID:32559291, PMID:32320679]. TENT4B is a determinant of HBV persistence: it physically associates with viral RNA and protects poly(A) tail integrity through the PRE stem-loop alpha element, and it is the cellular target of the HBV inhibitor RG7834, which engages its catalytic domain [PMID:30365161, PMID:33046485, PMID:34191584]. Dysregulated TENT4B is also pathogenic in Huntington's disease models, where YY1 sequestration derepresses PAPD5, increasing miRNA adenylation and activating a TAB2-TAK1-MKK4-JNK pro-apoptotic cascade that a small-molecule PAPD5 inhibitor mitigates [PMID:40204699].","teleology":[{"year":2011,"claim":"Established that PAPD5 is an autonomous RNA-adenylating enzyme, answering whether mammalian non-canonical poly(A) polymerases require a separate RNA-binding subunit as their yeast counterparts do.","evidence":"In vitro polyadenylation assays with recombinant PAPD5 plus C-terminal deletion analysis","pmids":["21788334"],"confidence":"High","gaps":["Did not identify physiological RNA substrates in cells","Catalytic versatility beyond adenylation not addressed"]},{"year":2012,"claim":"Defined a tailing-and-trimming logic for non-coding RNA maturation by showing PAPD5 oligoadenylates H/ACA snoRNA processing intermediates that PARN then trims.","evidence":"Reciprocal siRNA knockdown of PAPD5 and PARN with Northern blotting and 3'-end sequencing in human cells","pmids":["22442037"],"confidence":"High","gaps":["Substrate selectivity determinants unknown","Whether tailing promotes maturation versus degradation context-dependent"]},{"year":2014,"claim":"Extended PAPD5 adenylation to mature miRNAs, showing it adenylates miR-21 to trigger PARN-dependent 3'-to-5' decay and thereby relieve repression of target mRNAs.","evidence":"siRNA knockdown plus small-RNA sequencing of adenylated isomiRs and target mRNA microarray profiling","pmids":["25049417"],"confidence":"Medium","gaps":["Breadth of miRNA substrate repertoire not defined","Direct enzyme-substrate contact not shown in this system"]},{"year":2016,"claim":"Placed PAPD5 within a regulatory circuit by showing the intronic miR-4728-3p inhibits PAPD5 to stabilize miR-21, reinforcing the adenylation-then-degradation model.","evidence":"miRNA transfection/inhibition with PAPD5 activity and miR-21 abundance measurements","pmids":["27752128"],"confidence":"Medium","gaps":["Mechanism of PAPD5 inhibition by miR-4728-3p indirect","Single lab, builds on prior mechanism"]},{"year":2018,"claim":"Resolved how TENT4 enzymes stabilize rather than destabilize mRNA by demonstrating they synthesize mixed tails whose guanosine residues block CCR4-NOT deadenylation.","evidence":"Recombinant protein tail-synthesis assays, single-G insertion deadenylation assays, and knockdown half-life measurements","pmids":["30026317"],"confidence":"High","gaps":["What dictates guanosine versus adenosine incorporation in vivo unknown","Structural basis of CCR4-NOT impediment not resolved"]},{"year":2019,"claim":"Connected PAPD5 to telomere biology by showing it oligoadenylates TERC for EXOSC10 degradation, making its inhibition a strategy to rescue telomerase in DKC1-mutant cells.","evidence":"RNAi silencing in DKC1-mutant hESCs with TERC level, telomerase activity, and telomere length readouts, replicated across groups","pmids":["30728146","32559291","32320679"],"confidence":"High","gaps":["Recruitment of PAPD5 to TERC not mechanistically defined","Selectivity for TERC over other ncRNAs unexplained"]},{"year":2019,"claim":"Identified PAPD5/7 as the host targets of the HBV inhibitor RG7834 and as required for HBV RNA stability, establishing them as antiviral drug targets.","evidence":"Yeast three-hybrid target screen, catalytic-domain drug mapping, and siRNA knockdown phenocopy of HBV mRNA destabilization, replicated across labs","pmids":["30365161","33046485","34191584"],"confidence":"High","gaps":["Functional redundancy between PAPD5 and PAPD7 only partially partitioned","How viral RNA recruits the enzymes not yet defined here"]},{"year":2020,"claim":"Showed PAPD5/7 physically associate with HBV RNA and that blocking their activity shortens the viral poly(A) tail and accelerates decay, providing the mechanistic basis for RG7834 action.","evidence":"RNA co-immunoprecipitation, RG7834-sensitive polyadenylation assays, poly(A) tail analysis, and double-knockout cells","pmids":["33046485"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect RNA association not distinguished"]},{"year":2021,"claim":"Partitioned the roles of the two enzymes and mapped the cis-element, showing PAPD5 dominantly protects HBV poly(A) integrity via the PRE stem-loop alpha while PAPD7 is a backup.","evidence":"Individual/double CRISPR knockouts, poly(A) tail sequencing, and PRE stem-loop alpha mutagenesis","pmids":["34191584"],"confidence":"Medium","gaps":["Molecular contact between PAPD5 and stem-loop alpha not structurally resolved","Single lab"]},{"year":2025,"claim":"Implicated PAPD5 in neurodegeneration by showing YY1-driven derepression elevates PAPD5, increasing miRNA adenylation and activating a JNK pro-apoptotic pathway that an inhibitor reverses.","evidence":"HD cell and iPSC-neuron models with miRNA adenylation profiling, pathway epistasis, and BCH001 inhibitor rescue","pmids":["40204699"],"confidence":"Medium","gaps":["Causal chain from individual miRNAs to JNK activation not fully dissected","Single lab"]},{"year":2026,"claim":"Tested whether TENT4B has intrinsic synthetic capacity beyond templated tailing, showing it performs primer- and template-independent de novo RNA polymerization from free NTPs and NDPs.","evidence":"In vitro assays with recombinant TENT4B, pyrophosphate detection, labeled NTP incorporation, and primer-free product sequencing (preprint)","pmids":["41847027"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed and single lab","Physiological relevance of de novo synthesis in cells unknown","Self-limited guanosine polymerization mechanism unexplained"]},{"year":null,"claim":"How TENT4B selects between guanosine incorporation that stabilizes mRNA and oligoadenylation that targets ncRNAs for decay, and how it is recruited to specific substrates, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate selection or nucleotide choice","Recruitment mechanisms to TERC, snoRNAs, miRNAs, and HBV RNA undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,2,3,4,10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7,9]}],"complexes":[],"partners":["TENT4A","PARN","EXOSC10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NDF8","full_name":"Terminal nucleotidyltransferase 4B","aliases":["Non-canonical poly(A) RNA polymerase PAPD5","PAP-associated domain-containing protein 5","Terminal guanylyltransferase","Terminal uridylyltransferase 3","TUTase 3","Topoisomerase-related function protein 4-2","TRF4-2"],"length_aa":572,"mass_kda":63.3,"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:21788334, 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. Doesn't need a cofactor for polyadenylation activity (in vitro) (PubMed:21788334, PubMed:21855801). Required for cytoplasmic polyadenylation of mRNAs involved in carbohydrate metabolism, including the glucose transporter SLC2A1/GLUT1 (PubMed:28383716). Plays a role in replication-dependent histone mRNA degradation, probably through terminal uridylation of mature histone mRNAs. May play a role in sister chromatid cohesion (PubMed:18172165). Mediates 3' adenylation of the microRNA MIR21 followed by its 3'-to-5' trimming by the exoribonuclease PARN leading to degradation (PubMed:25049417). Mediates 3' adenylation of H/ACA box snoRNAs (small nucleolar RNAs) followed by its 3'-to-5' trimming by the exoribonuclease PARN which enhances snoRNA stability and maturation (PubMed:22442037)","subcellular_location":"Nucleus; Nucleus, nucleolus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8NDF8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TENT4B","classification":"Not Classified","n_dependent_lines":108,"n_total_lines":1208,"dependency_fraction":0.08940397350993377},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TENT4B","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":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TENT4B"},"hgnc":{"alias_symbol":["TRF4-2","TUT3"],"prev_symbol":["PAPD5"]},"alphafold":{"accession":"Q8NDF8","domains":[{"cath_id":"1.10.1410.10","chopping":"136-414","consensus_level":"medium","plddt":93.6215,"start":136,"end":414}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDF8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDF8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDF8-F1-predicted_aligned_error_v6.png","plddt_mean":70.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TENT4B","jax_strain_url":"https://www.jax.org/strain/search?query=TENT4B"},"sequence":{"accession":"Q8NDF8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NDF8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NDF8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDF8"}},"corpus_meta":[{"pmid":"22442037","id":"PMC_22442037","title":"Maturation of mammalian H/ACA box snoRNAs: PAPD5-dependent adenylation and PARN-dependent trimming.","date":"2012","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22442037","citation_count":134,"is_preprint":false},{"pmid":"30026317","id":"PMC_30026317","title":"Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30026317","citation_count":130,"is_preprint":false},{"pmid":"25049417","id":"PMC_25049417","title":"PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25049417","citation_count":129,"is_preprint":false},{"pmid":"32320679","id":"PMC_32320679","title":"Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells.","date":"2020","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/32320679","citation_count":78,"is_preprint":false},{"pmid":"30365161","id":"PMC_30365161","title":"PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization.","date":"2019","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/30365161","citation_count":74,"is_preprint":false},{"pmid":"21788334","id":"PMC_21788334","title":"PAPD5, a noncanonical poly(A) polymerase with an unusual RNA-binding motif.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21788334","citation_count":74,"is_preprint":false},{"pmid":"32559291","id":"PMC_32559291","title":"Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.","date":"2020","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/32559291","citation_count":36,"is_preprint":false},{"pmid":"30728146","id":"PMC_30728146","title":"Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30728146","citation_count":31,"is_preprint":false},{"pmid":"33046485","id":"PMC_33046485","title":"The Dihydroquinolizinone Compound RG7834 Inhibits the Polyadenylase Function of PAPD5 and PAPD7 and Accelerates the Degradation of Matured Hepatitis B Virus Surface Protein mRNA.","date":"2020","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/33046485","citation_count":27,"is_preprint":false},{"pmid":"34191584","id":"PMC_34191584","title":"Host Poly(A) Polymerases PAPD5 and PAPD7 Provide Two Layers of Protection That Ensure the Integrity and Stability of Hepatitis B Virus RNA.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34191584","citation_count":23,"is_preprint":false},{"pmid":"27752128","id":"PMC_27752128","title":"HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27752128","citation_count":18,"is_preprint":false},{"pmid":"32698757","id":"PMC_32698757","title":"Long noncoding RNA CASC2 inhibits ox-LDL-mediated vascular smooth muscle cells proliferation and migration via the regulation of miR-532-3p/PAPD5.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/32698757","citation_count":9,"is_preprint":false},{"pmid":"34807934","id":"PMC_34807934","title":"The EIF4E1-4EIP cap-binding complex of Trypanosoma brucei interacts with the terminal uridylyl transferase TUT3.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34807934","citation_count":7,"is_preprint":false},{"pmid":"40204699","id":"PMC_40204699","title":"Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40204699","citation_count":3,"is_preprint":false},{"pmid":"41847027","id":"PMC_41847027","title":"Primer- and template-independent RNA polymerization by terminal nucleotidyltransferase TENT4B.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41847027","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9555,"output_tokens":3281,"usd":0.03894,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10760,"output_tokens":3718,"usd":0.073375,"stage2_stop_reason":"end_turn"},"total_usd":0.112315,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"TENT4B (PAPD5) and TENT4A (PAPD7) are the enzymes responsible for mRNA guanylation; purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues (most commonly guanosine). A single guanosine residue in the tail is sufficient to impede the CCR4-NOT deadenylase complex, shielding mRNA from rapid deadenylation. Depletion of both TENT4A and TENT4B decreases mRNA half-life and abundance in cells.\",\n      \"method\": \"Biochemical purification of recombinant proteins, in vitro tail-synthesis assay, deadenylation assay with CCR4-NOT, siRNA knockdown with mRNA half-life measurement\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted enzymatic activity in vitro with purified proteins, mechanistic mutagenesis-equivalent single-G insertion assay, and cellular loss-of-function with defined phenotype, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"30026317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Recombinant PAPD5 catalyzes polyadenylation of diverse RNA substrates in vitro as a single polypeptide without a protein cofactor, in contrast to its yeast homolog Trf4p which requires a separate RNA-binding subunit. The C-terminal basic amino acid stretch of PAPD5 is involved in binding the RNA substrate.\",\n      \"method\": \"In vitro polyadenylation assay with recombinant PAPD5 expressed in mammalian cells and bacteria; deletion/domain analysis of C-terminal basic region\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic reconstitution with domain mutagenesis, single lab but multiple substrate conditions\",\n      \"pmids\": [\"21788334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAPD5 is responsible for adding oligo(A) tails to processing intermediates of H/ACA box snoRNAs (and scaRNAs) in human cells; these oligoadenylated intermediates are subsequently trimmed by PARN. Knockdown of PAPD5 abolishes accumulation of oligoadenylated snoRNA stubs. PARN is concentrated in nucleoli and Cajal bodies consistent with this role.\",\n      \"method\": \"siRNA knockdown of PAPD5 and PARN in human cells; Northern blotting and sequencing of snoRNA 3'-end intermediates; subcellular fractionation/immunofluorescence of PARN\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdown of writer (PAPD5) and eraser (PARN) with direct sequencing of modified RNA ends, two orthogonal methods, single lab\",\n      \"pmids\": [\"22442037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PAPD5 adenylates the 3' end of mature miR-21 in human cells; PAPD5 knockdown causes increased miR-21 levels, while PARN degrades adenylated miR-21 in the 3'-to-5' direction. This tailing-and-trimming pathway results in down-regulation of miR-21 target mRNAs.\",\n      \"method\": \"siRNA knockdown of PAPD5 and exoribonucleases; small-RNA sequencing to detect adenylated miR-21 isomiRs; microarray profiling of target mRNA expression changes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus small-RNA sequencing showing adenylated isomiRs, functional readout via target mRNA microarray, single lab\",\n      \"pmids\": [\"25049417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAPD5 (and PAPD7) oligoadenylates the telomerase RNA component TERC, destabilizing it. Knockdown or inhibition of PAPD5 in DKC1-mutant cells partially restores TERC levels and telomerase activity. The PAPD5–EXOSC10 axis mediates TERC degradation downstream of oligoadenylation.\",\n      \"method\": \"RNAi knockdown of PAPD5 in hESCs with DKC1_A353V mutation; measurement of TERC levels, telomerase activity, and telomere length; genetic silencing of PAPD5 as rescue experiment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (PAPD5 silencing) in disease-relevant hESC model with multiple functional readouts (TERC levels, telomerase activity, telomere elongation), replicated across two independent groups (PMIDs 30728146, 32559291, 32320679)\",\n      \"pmids\": [\"30728146\", \"32559291\", \"32320679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAPD5 and PAPD7 are identified as the cellular protein targets of the HBV inhibitor RG7834 via yeast three-hybrid screen; the drug interaction was mapped to the catalytic domains of both enzymes. PAPD5 and PAPD7 are required for HBV RNA stabilization: knockdown phenocopies RG7834 treatment by destabilizing HBV mRNA without affecting transcription, and simultaneous knockdown of both shows the greatest effect, indicating functional redundancy.\",\n      \"method\": \"Compound-based yeast three-hybrid screen; domain-mapping of RG7834 binding to catalytic domain; siRNA knockdown of PAPD5/7 in HBV-infected hepatocytes; HBV mRNA stability assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — target identification by protein-interaction screen plus domain mapping plus genetic knockdown phenocopy, replicated across multiple labs (PMIDs 30365161, 33046485, 34191584)\",\n      \"pmids\": [\"30365161\", \"33046485\", \"34191584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In HBV-expressing cells, PAPD5 and PAPD7 are physically associated with viral RNA. Inhibition of their polyadenylating activities by RG7834 leads to poly(A) tail shortening of HBV mRNA followed by accelerated nuclear and cytoplasmic degradation. In PAPD5/7 double-knockout cells, viral transcripts with normal poly(A) length can initially be synthesized but become shortened within hours.\",\n      \"method\": \"RNA co-immunoprecipitation (PAPD5/7 with HBV RNA); biochemical polyadenylation assay susceptibility to RG7834; poly(A) tail length analysis; PAPD5/7 double-knockout cell lines\",\n      \"journal\": \"Antimicrobial Agents and Chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA co-IP plus biochemical inhibition assay plus genetic knockout, single lab\",\n      \"pmids\": [\"33046485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAPD5 plays a dominant role in stabilizing HBV RNA by protecting the integrity of its poly(A) tail (PAPD5 KO impairs poly(A) tail integrity); PAPD7 serves as a second line of protection without measurable poly(A) tail effects alone. The stem-loop alpha sequence within the viral PRE is essential for maintaining poly(A) tail integrity and for sensitivity to PAPD5/7 inhibitors. Both PAPD5 and PAPD7 double-KO is required to reduce HBsAg production.\",\n      \"method\": \"Individual and double CRISPR knockout of PAPD5/7; poly(A) tail length sequencing; site-directed mutagenesis of viral PRE stem-loop alpha; inhibitor resistance assays\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with poly(A) tail sequencing and cis-element mutagenesis, single lab\",\n      \"pmids\": [\"34191584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-4728-3p (encoded in the HER2 intron) stabilizes miR-21-5p by inhibiting PAPD5, establishing that PAPD5-mediated 3' adenylation of miR-21-5p promotes its degradation in a PARN-dependent manner.\",\n      \"method\": \"miRNA transfection and inhibition experiments; PAPD5 expression and activity measurement after miR-4728-3p manipulation; miR-21-5p abundance assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — indirect regulation via miRNA inhibition of PAPD5 with downstream miR-21 abundance measurement, builds on prior PAPD5-miR-21 mechanism, single lab\",\n      \"pmids\": [\"27752128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Huntington's disease models, the transcriptional repressor YY1 is sequestered to RNA foci and protein aggregates, leading to derepression and upregulation of PAPD5. Elevated PAPD5 increases adenylation of a subset of miRNAs (including miR-7-5p), reducing their levels, which activates the TAB2-TAK1-MKK4-JNK pro-apoptotic pathway and causes neuronal death. A small-molecule PAPD5 inhibitor (BCH001) mitigates this cell death.\",\n      \"method\": \"HD cell and iPSC-derived neuron models; PAPD5 expression and miRNA adenylation profiling; YY1 localization studies; TAK1-MKK4-JNK pathway activation assays; BCH001 inhibitor rescue experiments in disease models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (inhibitor) plus mechanistic pathway epistasis in multiple HD models including patient-derived neurons, single lab\",\n      \"pmids\": [\"40204699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Recombinant TENT4B can perform primer- and template-independent de novo RNA polymerization from free NTPs, consuming ATP to yield inorganic pyrophosphate and oligomeric poly-adenosine RNA products. The de novo synthesis efficiency is similar whether or not a primer is included. Guanosine nucleotide polymerization is self-limited and yields a 3'-exonuclease-resistant oligonucleotide. Nucleotide diphosphates can also serve as substrates.\",\n      \"method\": \"In vitro biochemical assay with recombinant TENT4B; ATP consumption / pyrophosphate detection; 5'-radiolabeled γ-phosphate-modified NTP incorporation; primer-free RNA product sequencing; comparison across NTP types and concentrations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro reconstitution with recombinant enzyme and multiple substrate conditions, but preprint/single lab, not yet peer-reviewed\",\n      \"pmids\": [\"41847027\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TENT4B (PAPD5) is a non-canonical poly(A) polymerase that adds mixed adenosine/guanosine tails to mRNAs to shield them from CCR4-NOT-mediated deadenylation, oligoadenylates H/ACA box snoRNA processing intermediates and mature miRNAs (including miR-21) to promote their PARN-dependent trimming or degradation, oligoadenylates TERC to target it for exosome-mediated degradation, stabilizes HBV RNA by protecting viral poly(A) tail integrity via physical association with viral PRE, and can also perform primer- and template-independent de novo RNA synthesis in vitro.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TENT4B (PAPD5) is a non-canonical poly(A) polymerase that controls RNA stability in opposite directions depending on substrate, acting as a single-polypeptide enzyme that binds RNA through its C-terminal basic region and polymerizes nucleotides without an accessory RNA-binding cofactor [#1]. On mRNA, TENT4B (together with TENT4A) builds mixed poly(A) tails in which intermittent non-adenosine residues — most commonly guanosine — are interspersed; a single guanosine is sufficient to stall the CCR4-NOT deadenylase, so this guanylation shields transcripts from rapid deadenylation and sustains mRNA half-life and abundance [#0]. The same adenylating activity instead marks several non-coding RNAs for turnover: TENT4B adds oligo(A) tails to H/ACA box snoRNA/scaRNA processing intermediates that are then trimmed by PARN [#2], adenylates mature miR-21 and other miRNAs to drive their PARN-dependent degradation [#3], and oligoadenylates the telomerase RNA TERC to route it for EXOSC10-mediated decay, such that silencing TENT4B in DKC1-mutant cells restores TERC, telomerase activity, and telomere length [#4]. TENT4B is a determinant of HBV persistence: it physically associates with viral RNA and protects poly(A) tail integrity through the PRE stem-loop alpha element, and it is the cellular target of the HBV inhibitor RG7834, which engages its catalytic domain [#5, #6, #7]. Dysregulated TENT4B is also pathogenic in Huntington's disease models, where YY1 sequestration derepresses PAPD5, increasing miRNA adenylation and activating a TAB2-TAK1-MKK4-JNK pro-apoptotic cascade that a small-molecule PAPD5 inhibitor mitigates [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that PAPD5 is an autonomous RNA-adenylating enzyme, answering whether mammalian non-canonical poly(A) polymerases require a separate RNA-binding subunit as their yeast counterparts do.\",\n      \"evidence\": \"In vitro polyadenylation assays with recombinant PAPD5 plus C-terminal deletion analysis\",\n      \"pmids\": [\"21788334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological RNA substrates in cells\", \"Catalytic versatility beyond adenylation not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a tailing-and-trimming logic for non-coding RNA maturation by showing PAPD5 oligoadenylates H/ACA snoRNA processing intermediates that PARN then trims.\",\n      \"evidence\": \"Reciprocal siRNA knockdown of PAPD5 and PARN with Northern blotting and 3'-end sequencing in human cells\",\n      \"pmids\": [\"22442037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selectivity determinants unknown\", \"Whether tailing promotes maturation versus degradation context-dependent\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PAPD5 adenylation to mature miRNAs, showing it adenylates miR-21 to trigger PARN-dependent 3'-to-5' decay and thereby relieve repression of target mRNAs.\",\n      \"evidence\": \"siRNA knockdown plus small-RNA sequencing of adenylated isomiRs and target mRNA microarray profiling\",\n      \"pmids\": [\"25049417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of miRNA substrate repertoire not defined\", \"Direct enzyme-substrate contact not shown in this system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed PAPD5 within a regulatory circuit by showing the intronic miR-4728-3p inhibits PAPD5 to stabilize miR-21, reinforcing the adenylation-then-degradation model.\",\n      \"evidence\": \"miRNA transfection/inhibition with PAPD5 activity and miR-21 abundance measurements\",\n      \"pmids\": [\"27752128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PAPD5 inhibition by miR-4728-3p indirect\", \"Single lab, builds on prior mechanism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how TENT4 enzymes stabilize rather than destabilize mRNA by demonstrating they synthesize mixed tails whose guanosine residues block CCR4-NOT deadenylation.\",\n      \"evidence\": \"Recombinant protein tail-synthesis assays, single-G insertion deadenylation assays, and knockdown half-life measurements\",\n      \"pmids\": [\"30026317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates guanosine versus adenosine incorporation in vivo unknown\", \"Structural basis of CCR4-NOT impediment not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PAPD5 to telomere biology by showing it oligoadenylates TERC for EXOSC10 degradation, making its inhibition a strategy to rescue telomerase in DKC1-mutant cells.\",\n      \"evidence\": \"RNAi silencing in DKC1-mutant hESCs with TERC level, telomerase activity, and telomere length readouts, replicated across groups\",\n      \"pmids\": [\"30728146\", \"32559291\", \"32320679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment of PAPD5 to TERC not mechanistically defined\", \"Selectivity for TERC over other ncRNAs unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified PAPD5/7 as the host targets of the HBV inhibitor RG7834 and as required for HBV RNA stability, establishing them as antiviral drug targets.\",\n      \"evidence\": \"Yeast three-hybrid target screen, catalytic-domain drug mapping, and siRNA knockdown phenocopy of HBV mRNA destabilization, replicated across labs\",\n      \"pmids\": [\"30365161\", \"33046485\", \"34191584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy between PAPD5 and PAPD7 only partially partitioned\", \"How viral RNA recruits the enzymes not yet defined here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PAPD5/7 physically associate with HBV RNA and that blocking their activity shortens the viral poly(A) tail and accelerates decay, providing the mechanistic basis for RG7834 action.\",\n      \"evidence\": \"RNA co-immunoprecipitation, RG7834-sensitive polyadenylation assays, poly(A) tail analysis, and double-knockout cells\",\n      \"pmids\": [\"33046485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect RNA association not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Partitioned the roles of the two enzymes and mapped the cis-element, showing PAPD5 dominantly protects HBV poly(A) integrity via the PRE stem-loop alpha while PAPD7 is a backup.\",\n      \"evidence\": \"Individual/double CRISPR knockouts, poly(A) tail sequencing, and PRE stem-loop alpha mutagenesis\",\n      \"pmids\": [\"34191584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular contact between PAPD5 and stem-loop alpha not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PAPD5 in neurodegeneration by showing YY1-driven derepression elevates PAPD5, increasing miRNA adenylation and activating a JNK pro-apoptotic pathway that an inhibitor reverses.\",\n      \"evidence\": \"HD cell and iPSC-neuron models with miRNA adenylation profiling, pathway epistasis, and BCH001 inhibitor rescue\",\n      \"pmids\": [\"40204699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from individual miRNAs to JNK activation not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tested whether TENT4B has intrinsic synthetic capacity beyond templated tailing, showing it performs primer- and template-independent de novo RNA polymerization from free NTPs and NDPs.\",\n      \"evidence\": \"In vitro assays with recombinant TENT4B, pyrophosphate detection, labeled NTP incorporation, and primer-free product sequencing (preprint)\",\n      \"pmids\": [\"41847027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed and single lab\", \"Physiological relevance of de novo synthesis in cells unknown\", \"Self-limited guanosine polymerization mechanism unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TENT4B selects between guanosine incorporation that stabilizes mRNA and oligoadenylation that targets ncRNAs for decay, and how it is recruited to specific substrates, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate selection or nucleotide choice\", \"Recruitment mechanisms to TERC, snoRNAs, miRNAs, and HBV RNA undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TENT4A\", \"PARN\", \"EXOSC10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}