{"gene":"TUT7","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2012,"finding":"TUT7 (Zcchc6) functions as an alternative TUTase to TUT4 (Zcchc11) in Lin28-mediated pre-let-7 uridylation; a single C2H2-type zinc finger domain of Zcchc11 is responsible for functional interaction with Lin28, and Zcchc11/Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells.","method":"Biochemical dissection and reconstitution assays, in vitro uridylation assays, domain-deletion analysis, embryonic stem cell depletion experiments","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution assays plus domain mutagenesis, replicated across multiple orthogonal methods in one study","pmids":["22898984"],"is_preprint":false},{"year":2014,"finding":"TUT7 (Zcchc6) and TUT4 (Zcchc11) selectively mono-uridylate a specific subset of mature miRNAs involved in cell differentiation and Hox gene control; a bipartite sequence motif in the miRNA is necessary and sufficient for Zcchc6/11-catalyzed uridylation; TUTase depletion leads to loss of 3' mono-uridylation and a concomitant increase in non-templated 3' mono-adenylation.","method":"In vitro uridylation assays, biochemical motif definition, siRNA knockdown in cultured cells with deep sequencing, zebrafish developmental perturbation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemistry defining sequence motif, orthogonal cell-based knockdown and sequencing, plus in vivo zebrafish validation","pmids":["25223788"],"is_preprint":false},{"year":2015,"finding":"TUT7 uses three mechanistically distinct uridylation modes for pre-miRNAs depending on 3'-overhang structure: (1) mono-uridylation of group II pre-miRNAs (1-nt 3' overhang) to restore canonical 2-nt overhang and promote biogenesis; (2) oligo-uridylation of 3'-trimmed (recessed) pre-miRNAs to mark them for degradation; (3) in the absence of Lin28, both modes are distributive (not processive), and overhang length dictates frequency—but not duration—of TUT7-RNA interaction.","method":"Biochemistry (in vitro uridylation assays), single-molecule experiments, deep sequencing","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (in vitro biochemistry, single-molecule, deep sequencing) in one rigorous study","pmids":["25979828"],"is_preprint":false},{"year":2016,"finding":"TUT7 is the primary TUTase responsible for oligouridylation at the 3' end of histone mRNAs and of degradation intermediates within the stem-loop during histone mRNA degradation; TUT7 and 3'hExo function together in trimming and uridylating histone mRNAs. Knockdown of TUT4 did not alter the uridylation pattern at the 3' end.","method":"siRNA knockdown of TUT7 and TUT4 followed by high-throughput sequencing of histone mRNAs and degradation intermediates","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with deep sequencing readout, single lab, but two enzymes compared","pmids":["27609902"],"is_preprint":false},{"year":2017,"finding":"TUT4 and TUT7 utilize two multidomain functional modules to switch between mono-uridylation (promoting let-7 expression) and oligo-uridylation (marking for degradation): a catalytic module (CM) essential for both activities and a Lin28-interacting module (LIM) indispensable for oligo-uridylation. A crystal structure of the TUT7 CM in the mono-uridylation state reveals a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins to favor monoU addition. The ZK domain of Lin28 drives formation of a stable ternary complex with pre-let-7 and the inactive LIM, and ZK2 of TUT4/7 engages the growing oligoU tail through uracil-specific interactions.","method":"Crystal structure determination of TUT7 CM, domain deletion/mutagenesis, in vitro uridylation assays, biochemical complex reconstitution","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus reconstitution and mutagenesis, multiple orthogonal methods in one study","pmids":["28671666"],"is_preprint":false},{"year":2017,"finding":"Zcchc6 (TUT7) is expressed in mouse and human primary macrophages; Zcchc6-deficient macrophages exhibit increased expression of select cytokines (IL-6, CXCL1, CXCL5) following bacterial (S. pneumoniae) stimulation, indicating TUT7 has a suppressive role in macrophage innate immune cytokine responses.","method":"Zcchc6 knockout mouse generation, intratracheal bacterial challenge, in vitro macrophage stimulation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, single lab","pmids":["28665939"],"is_preprint":false},{"year":2019,"finding":"ZCCHC6 (TUT7) enhances IL-6 expression in chondrocytes by (1) stabilizing the IL-6 transcript and (2) uridylating miR-26b, which abrogates miR-26b-mediated repression of IL-6. Zcchc6 knockout mice with surgically induced osteoarthritis show reduced IL-6 levels and reduced cartilage damage.","method":"siRNA knockdown and overexpression in human chondrocytes, actinomycin D chase for mRNA stability, deep sequencing for miRNA 3'-uridylation, Zcchc6 knockout mouse model with surgical OA induction, Zcchc6 rescue in KO chondrocytes","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, overexpression, KO mouse, mRNA stability assay, deep sequencing, rescue), single lab but comprehensive","pmids":["30302948"],"is_preprint":false},{"year":2022,"finding":"TUT7 knockout in HEK293T cells reveals that TUT4 uridylates most miRNAs whereas TUT7 alone is dispensable for bulk miRNA uridylation; however, specific miRNAs (miR-888 cluster) are upregulated specifically by TUT7, indicating selective substrate control. Abolishing uridylation (TUT4/7 double KO) dysregulates a defined set of miRNAs including let-7, miR-181b, and miR-222.","method":"CRISPR knockout of TENT2, TUT4, TUT7 individually and in combination in isogenic HEK293T lines, deep sequencing, Northern blot, in vitro assays, rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — isogenic CRISPR KO lines with multiple orthogonal methods and rescue experiments","pmids":["36071058"],"is_preprint":false},{"year":2022,"finding":"TUT7 (TENT3B/ZCCHC6) specifically uridylates histone mRNA degradation intermediates in the stem-loop region; knockout of TUT7 prevents uridylation of these intermediates and slows the rate of histone mRNA degradation without blocking initiation. TUT7 and 3'hExo cooperate: 3'hExo initiates degradation and maintains histone mRNA 3'-end length while TUT7 uridylates intermediates to facilitate complete degradation.","method":"TUT7 and 3'hExo CRISPR knockout in human cells, cell synchronization, high-throughput sequencing of histone mRNA degradation intermediates","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KOs with deep sequencing and cell synchronization, replicates and extends earlier knockdown findings","pmids":["36041871"],"is_preprint":false},{"year":2024,"finding":"TUT7 functions as a salvage RNA decay mechanism in FOCAD-deleted cancer cells: FOCAD loss destabilizes the SKI complex, and TUT7 (together with DIS3L2) then degrades aberrant RNA; genetic or pharmacologic inhibition of TUT7 selectively kills FOCAD-deleted cancer cells. TUT7 knockout (but not TUT4 knockout) impairs proliferation in FOCAD-loss cancer cells, indicating non-redundant roles.","method":"CRISPR knockout of TUT7, TUT4, DIS3L2, and FOCAD; functional genomics data analysis; first potent/selective TUT4/7 small-molecule inhibitors with in vitro and in vivo antiproliferative assays; FOCAD reintroduction rescue experiment","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO epistasis, pharmacological inhibitors, in vivo data, and genetic rescue, multiple orthogonal methods","pmids":["39235218"],"is_preprint":false},{"year":2024,"finding":"TUT7-mediated uridylation of mature miR-1246 promotes its degradation as a small noncoding RNA (not from the precursor miR-1246), and this process is stabilized by SNRPB; this leads to accumulation of exosomal miR-1246 in colorectal cancer, which drives TAM polarization and CD8+ T cell suppression.","method":"Co-culture macrophage education system, TUT7 functional characterization, database mining validated by in vitro experiments, RNA-seq","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism described at abstract level without detailed in vitro reconstitution; abstract is not fully explicit about TUT7-specific assays","pmids":["38342611"],"is_preprint":false},{"year":2025,"finding":"TUT7 (and TUT4) uridylate the 5' cleavage fragment generated by KHNYN endonuclease cleavage of viral RNA during ZAP-mediated RNA decay (ZMD); the uridylated fragment is then degraded by DIS3L2. TUT7 interacts with ZAP and TRIM25 in a RNase-resistant manner, and viral infection promotes TRIM25 interaction with TUT7.","method":"RNase-resistant co-immunoprecipitation, ordered pathway dissection, overexpression and interaction studies in ZMD pathway reconstitution (preprint)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pathway reconstitution with ordered epistasis, single preprint study","pmids":["bio_10.1101_2025.04.28.650959"],"is_preprint":true},{"year":2025,"finding":"TUT7 reduces the stability of MCPIP1 mRNA through uridylation (demonstrated by in vitro transcription and uridylation experiments), thereby weakening MCPIP1-mediated suppression of pterygium fibroblast autophagy and fibrosis.","method":"In vitro transcription and uridylation assays, co-immunoprecipitation, Western blot, qRT-PCR, immunohistochemistry, transwell migration and wound-healing assays, immunofluorescence","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro uridylation assay plus multiple cellular assays, single lab","pmids":["40238115"],"is_preprint":false}],"current_model":"TUT7 (ZCCHC6/ZCCHC11 paralog) is a terminal uridylyl transferase that operates via three mechanistically distinct modes—Lin28-stimulated processive oligo-uridylation to suppress let-7 biogenesis, distributive mono-uridylation to repair group II pre-miRNAs, and oligo-uridylation of trimmed pre-miRNAs or mRNA degradation intermediates to promote their decay—and its catalytic module (structurally resolved) plus a Lin28-interacting module govern switching between these activities; beyond miRNA regulation, TUT7 is the primary TUTase for uridylating histone mRNA 3' ends and degradation intermediates in cooperation with 3'hExo, it uridylates specific mature miRNAs (including miR-26b and miR-1246) to modulate inflammatory gene expression, it acts as a salvage RNA decay enzyme for aberrant transcripts in FOCAD-deficient cells together with DIS3L2, and it is recruited by the ZAP/TRIM25 complex to uridylate viral RNA fragments for antiviral defense."},"narrative":{"mechanistic_narrative":"TUT7 (ZCCHC6/TENT3B) is a terminal uridylyl transferase that controls RNA fate by adding non-templated uridines to the 3' ends of small RNAs, mRNAs, and decay intermediates, acting redundantly with or independently of its paralog TUT4 depending on substrate [PMID:22898984, PMID:36071058]. In let-7 biogenesis it operates through two structurally and kinetically distinct modes dictated by pre-miRNA 3'-overhang structure: distributive mono-uridylation of group II pre-miRNAs restores a canonical 2-nucleotide overhang to promote maturation, while oligo-uridylation of 3'-trimmed precursors marks them for degradation [PMID:25979828]. Mode switching is governed by two functional modules—a catalytic module whose crystal structure reveals a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins for mono-U addition, and a Lin28-interacting module that, engaged by the Lin28 ZK domain, forms a stable ternary complex enabling processive oligo-uridylation [PMID:28671666]. TUT7 also recognizes a bipartite sequence motif to mono-uridylate a specific subset of mature miRNAs, with depletion shifting the 3' end toward mono-adenylation [PMID:25223788]. Beyond miRNA control, TUT7 is the primary TUTase uridylating histone mRNA 3' ends and stem-loop degradation intermediates in cooperation with the 3'→5' exonuclease 3'hExo to drive complete histone mRNA decay [PMID:27609902, PMID:36041871], and it serves as a salvage decay enzyme acting with DIS3L2 to clear aberrant transcripts in FOCAD-deficient cells, where its loss is selectively lethal [PMID:39235218]. Through targeted uridylation of specific mature miRNAs (miR-26b) and mRNAs (IL-6), TUT7 modulates inflammatory and tissue-remodeling gene expression and contributes to phenotypes including osteoarthritic cartilage damage [PMID:30302948].","teleology":[{"year":2012,"claim":"Established that TUT7 is a bona fide uridylyl transferase that, like TUT4, interacts with Lin28 to uridylate pre-let-7 and that the two enzymes redundantly control let-7 biogenesis, defining TUT7's founding role in the Lin28/let-7 axis.","evidence":"In vitro uridylation and reconstitution assays, domain-deletion mapping of a C2H2 zinc finger, and ES cell depletion","pmids":["22898984"],"confidence":"High","gaps":["Did not resolve the structural basis of catalysis or substrate discrimination","Degree of substrate-specific division of labor between TUT4 and TUT7 left open"]},{"year":2014,"claim":"Showed TUT7/TUT4 selectively mono-uridylate a defined subset of mature miRNAs via a bipartite sequence motif, revealing sequence-specific substrate recognition and an antagonism with 3' adenylation.","evidence":"In vitro motif-definition biochemistry, siRNA knockdown with deep sequencing, and zebrafish developmental perturbation","pmids":["25223788"],"confidence":"High","gaps":["Did not establish how the motif is read structurally","Functional consequences of mono-U vs mono-A on individual miRNAs not fully resolved"]},{"year":2015,"claim":"Resolved the mechanistic logic of TUT7 mode-switching, showing 3'-overhang structure dictates mono- versus oligo-uridylation and that, absent Lin28, both modes are distributive with overhang length controlling interaction frequency.","evidence":"In vitro uridylation assays, single-molecule experiments, and deep sequencing","pmids":["25979828"],"confidence":"High","gaps":["Structural basis for overhang discrimination not yet visualized","How Lin28 converts distributive to processive activity left for later work"]},{"year":2016,"claim":"Identified TUT7 as the primary TUTase uridylating histone mRNA 3' ends and stem-loop degradation intermediates, distinguishing it functionally from TUT4 and linking it to histone mRNA turnover with 3'hExo.","evidence":"siRNA knockdown of TUT7 and TUT4 with high-throughput sequencing of histone mRNAs","pmids":["27609902"],"confidence":"Medium","gaps":["Knockdown rather than knockout; residual enzyme possible","Direct physical cooperation with 3'hExo not biochemically reconstituted here"]},{"year":2017,"claim":"Defined the modular and structural basis of TUT7 activity by solving the catalytic module crystal structure in the mono-uridylation state and mapping a Lin28-interacting module required specifically for oligo-uridylation, explaining mode switching at atomic resolution.","evidence":"Crystal structure of the TUT7 catalytic module, domain mutagenesis, in vitro assays, and ternary complex reconstitution","pmids":["28671666"],"confidence":"High","gaps":["No full-length structure including the LIM in the active oligo-U state","Structural transitions during processive synthesis not captured"]},{"year":2017,"claim":"Connected TUT7 to innate immunity, showing macrophage TUT7 suppresses select cytokine responses to bacterial challenge, extending its role beyond RNA biogenesis into immune regulation.","evidence":"Zcchc6 knockout mice, intratracheal bacterial challenge, and macrophage stimulation assays","pmids":["28665939"],"confidence":"Medium","gaps":["RNA substrate(s) mediating the cytokine phenotype not identified","Catalytic dependence of the immune effect not directly tested"]},{"year":2019,"claim":"Demonstrated a dual mechanism by which TUT7 amplifies IL-6 expression—stabilizing the IL-6 transcript and uridylating miR-26b to relieve its repression of IL-6—and linked this to osteoarthritis pathology in vivo.","evidence":"Chondrocyte knockdown/overexpression, actinomycin D mRNA-stability chase, miRNA uridylation sequencing, and a surgical osteoarthritis KO mouse model with rescue","pmids":["30302948"],"confidence":"High","gaps":["Mechanism by which miR-26b uridylation abrogates repression not detailed","Generality of TUT7-mediated mRNA stabilization beyond IL-6 unclear"]},{"year":2022,"claim":"Using isogenic CRISPR knockouts, established the division of labor between TUT4 and TUT7—TUT4 drives bulk miRNA uridylation while TUT7 selectively controls specific miRNAs (miR-888 cluster)—and defined a uridylation-dependent miRNA set including let-7, miR-181b, and miR-222.","evidence":"CRISPR knockout of TENT2/TUT4/TUT7 alone and combined, deep sequencing, Northern blot, in vitro assays, and rescue","pmids":["36071058"],"confidence":"High","gaps":["Basis for TUT7's selectivity toward specific miRNAs not mechanistically explained","Functional consequences for each dysregulated miRNA not all defined"]},{"year":2022,"claim":"Confirmed via knockout that TUT7 uridylation of histone mRNA stem-loop degradation intermediates accelerates complete decay and that TUT7 cooperates with 3'hExo, which initiates trimming and sets 3'-end length.","evidence":"CRISPR knockout of TUT7 and 3'hExo, cell synchronization, and deep sequencing of degradation intermediates","pmids":["36041871"],"confidence":"High","gaps":["Direct physical interaction and ordering of TUT7/3'hExo not structurally resolved","Downstream nuclease completing decay of uridylated intermediates not defined here"]},{"year":2024,"claim":"Revealed a synthetic-lethal salvage RNA decay role in which FOCAD loss destabilizes the SKI complex and makes cells dependent on TUT7 (with DIS3L2) to clear aberrant RNA, nominating TUT7 as a selective cancer target and yielding first-in-class TUT4/7 inhibitors.","evidence":"CRISPR knockout epistasis (TUT7/TUT4/DIS3L2/FOCAD), functional genomics, FOCAD-reintroduction rescue, and small-molecule inhibitors with in vivo antiproliferative assays","pmids":["39235218"],"confidence":"High","gaps":["Identity of the aberrant transcripts salvaged by TUT7 not enumerated","Mechanism rendering TUT7 non-redundant with TUT4 in this context unresolved"]},{"year":2024,"claim":"Proposed that TUT7 uridylates mature miR-1246 to promote its turnover, with SNRPB stabilization shaping exosomal miR-1246 levels that drive tumor-associated macrophage polarization and T cell suppression in colorectal cancer.","evidence":"Macrophage co-culture education system, TUT7 functional characterization, RNA-seq, and database mining","pmids":["38342611"],"confidence":"Low","gaps":["Mechanism described at abstract level without detailed TUT7-specific in vitro reconstitution","Direct enzymatic action on mature miR-1246 not biochemically isolated","SNRPB–TUT7 relationship not mechanistically defined"]},{"year":2025,"claim":"Placed TUT7 within antiviral ZAP-mediated RNA decay, showing it uridylates the 5' KHNYN-cleavage fragment of viral RNA for DIS3L2 degradation and physically associates with ZAP and TRIM25 in an infection-enhanced, RNase-resistant manner.","evidence":"RNase-resistant co-immunoprecipitation, ordered pathway dissection, and ZMD reconstitution (preprint)","pmids":["bio_10.1101_2025.04.28.650959"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Structural basis of ZAP/TRIM25–TUT7 recruitment unresolved","Relative contributions of TUT4 vs TUT7 in ZMD not separated"]},{"year":2025,"claim":"Extended TUT7's mRNA-destabilizing activity to MCPIP1, showing uridylation lowers MCPIP1 transcript stability and thereby modulates autophagy and fibrosis in pterygium fibroblasts.","evidence":"In vitro transcription/uridylation assays, co-IP, Western blot, qRT-PCR, and cellular migration/wound-healing assays","pmids":["40238115"],"confidence":"Medium","gaps":["Single-lab study in a specialized cell context","Generality of TUT7-mediated mRNA destabilization across tissues unclear"]},{"year":null,"claim":"How TUT7 achieves substrate selectivity across its diverse RNA targets—miRNAs, histone mRNAs, mRNAs, and viral fragments—and what determines its non-redundant versus redundant relationship with TUT4 in each pathway remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model explaining differential substrate engagement","Cofactors/adaptors directing TUT7 to specific decay vs biogenesis pathways largely unmapped","Full-length enzyme structure in oligo-uridylation state lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,4,7]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,3,8]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,11]}],"complexes":[],"partners":["LIN28","3'HEXO","DIS3L2","ZAP","TRIM25","SNRPB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VYS8","full_name":"Terminal uridylyltransferase 7","aliases":["Zinc finger CCHC domain-containing protein 6"],"length_aa":1495,"mass_kda":171.2,"function":"Uridylyltransferase that mediates the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay (PubMed:19703396, PubMed:25480299). Essential for both oocyte maturation and fertility. Through 3' terminal uridylation of mRNA, sculpts, with TUT7, the maternal transcriptome by eliminating transcripts during oocyte growth (By similarity). Involved in microRNA (miRNA)-induced gene silencing through uridylation of deadenylated miRNA targets (PubMed:25480299). Also functions as an integral regulator of microRNA biogenesiS using 3 different uridylation mechanisms (PubMed:25979828). Acts as a suppressor of miRNA biogenesis by mediating the terminal uridylation of some miRNA precursors, including that of let-7 (pre-let-7). Uridylated pre-let-7 RNA is not processed by Dicer and undergo degradation. Pre-let-7 uridylation is strongly enhanced in the presence of LIN28A (PubMed:22898984). In the absence of LIN28A, TUT7 and TUT4 monouridylate group II pre-miRNAs, which includes most of pre-let7 members, that shapes an optimal 3' end overhang for efficient processing (PubMed:25979828, PubMed:28671666). Add oligo-U tails to truncated pre-miRNAS with a 5' overhang which may promote rapid degradation of non-functional pre-miRNA species (PubMed:25979828). Does not play a role in replication-dependent histone mRNA degradation (PubMed:18172165). Due to functional redundancy between TUT4 and TUT7, the identification of the specific role of each of these proteins is difficult (PubMed:18172165, PubMed:19703396, PubMed:22898984, PubMed:25480299, PubMed:25979828, PubMed:28671666). TUT4 and TUT7 restrict retrotransposition of long interspersed element-1 (LINE-1) in cooperation with MOV10 counteracting the RNA chaperonne activity of L1RE1. TUT7 uridylates LINE-1 mRNAs in the cytoplasm which inhibits initiation of reverse transcription once in the nucleus, whereas uridylation by TUT4 destabilizes mRNAs in cytoplasmic ribonucleoprotein granules (PubMed:30122351)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5VYS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TUT7","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TUT7","total_profiled":1310},"omim":[{"mim_id":"613692","title":"TERMINAL URIDYLYL TRANSFERASE 4; TUT4","url":"https://www.omim.org/entry/613692"},{"mim_id":"613467","title":"ZINC FINGER CCHC DOMAIN-CONTAINING PROTEIN 6; ZCCHC6","url":"https://www.omim.org/entry/613467"},{"mim_id":"611043","title":"LIN28 HOMOLOG A; LIN28A","url":"https://www.omim.org/entry/611043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TUT7"},"hgnc":{"alias_symbol":["KIAA1711","FLJ13409","PAPD6","TENT3B"],"prev_symbol":["ZCCHC6"]},"alphafold":{"accession":"Q5VYS8","domains":[{"cath_id":"-","chopping":"217-284","consensus_level":"high","plddt":88.6266,"start":217,"end":284},{"cath_id":"1.10.1410.10","chopping":"290-514_532-631","consensus_level":"medium","plddt":91.1291,"start":290,"end":631},{"cath_id":"3.30.460.10","chopping":"1014-1132","consensus_level":"medium","plddt":94.4326,"start":1014,"end":1132},{"cath_id":"1.10.1410.10","chopping":"1141-1360","consensus_level":"medium","plddt":94.5017,"start":1141,"end":1360}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VYS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VYS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VYS8-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TUT7","jax_strain_url":"https://www.jax.org/strain/search?query=TUT7"},"sequence":{"accession":"Q5VYS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VYS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VYS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VYS8"}},"corpus_meta":[{"pmid":"22898984","id":"PMC_22898984","title":"Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7).","date":"2012","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22898984","citation_count":176,"is_preprint":false},{"pmid":"25979828","id":"PMC_25979828","title":"TUT7 controls the fate of precursor microRNAs by using three different uridylation mechanisms.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25979828","citation_count":89,"is_preprint":false},{"pmid":"25223788","id":"PMC_25223788","title":"Selective microRNA uridylation by Zcchc6 (TUT7) and Zcchc11 (TUT4).","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25223788","citation_count":85,"is_preprint":false},{"pmid":"28671666","id":"PMC_28671666","title":"Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis.","date":"2017","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28671666","citation_count":45,"is_preprint":false},{"pmid":"36071058","id":"PMC_36071058","title":"TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36071058","citation_count":44,"is_preprint":false},{"pmid":"27609902","id":"PMC_27609902","title":"TUT7 catalyzes the uridylation of the 3' end for rapid degradation of histone mRNA.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27609902","citation_count":41,"is_preprint":false},{"pmid":"30302948","id":"PMC_30302948","title":"Genetic Inactivation of ZCCHC6 Suppresses Interleukin-6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice.","date":"2019","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30302948","citation_count":31,"is_preprint":false},{"pmid":"38342611","id":"PMC_38342611","title":"The Uridylyl Transferase TUT7-Mediated Accumulation of Exosomal miR-1246 Reprograms TAMs to Support CRC Progression.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38342611","citation_count":19,"is_preprint":false},{"pmid":"28665939","id":"PMC_28665939","title":"The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28665939","citation_count":17,"is_preprint":false},{"pmid":"39235218","id":"PMC_39235218","title":"Targeting the Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer.","date":"2024","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39235218","citation_count":5,"is_preprint":false},{"pmid":"36041871","id":"PMC_36041871","title":"Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation.","date":"2022","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36041871","citation_count":4,"is_preprint":false},{"pmid":"9279345","id":"PMC_9279345","title":"[Menogaril (TUT-7) late phase II study for malignant lymphoma, adult T-cell leukemia and lymphoma (ATLL)].","date":"1997","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/9279345","citation_count":4,"is_preprint":false},{"pmid":"32526260","id":"PMC_32526260","title":"Induction of ZCCHC6 expression in peripheral blood mononuclear cells by HNSCC secretions.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32526260","citation_count":3,"is_preprint":false},{"pmid":"40238115","id":"PMC_40238115","title":"TUT7-Mediated Uridine Degradation of MCPIP1 in the Pterygium to Regulate TRAF6-Mediated Autophagy.","date":"2025","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/40238115","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.28.650959","title":"The long isoform of ZAP coordinates multiple enzymes to mediate complete decay of target transcripts","date":"2025-05-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.650959","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9579,"output_tokens":3804,"usd":0.042898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11432,"output_tokens":4673,"usd":0.086993,"stage2_stop_reason":"end_turn"},"total_usd":0.129891,"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\": 2012,\n      \"finding\": \"TUT7 (Zcchc6) functions as an alternative TUTase to TUT4 (Zcchc11) in Lin28-mediated pre-let-7 uridylation; a single C2H2-type zinc finger domain of Zcchc11 is responsible for functional interaction with Lin28, and Zcchc11/Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells.\",\n      \"method\": \"Biochemical dissection and reconstitution assays, in vitro uridylation assays, domain-deletion analysis, embryonic stem cell depletion experiments\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution assays plus domain mutagenesis, replicated across multiple orthogonal methods in one study\",\n      \"pmids\": [\"22898984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TUT7 (Zcchc6) and TUT4 (Zcchc11) selectively mono-uridylate a specific subset of mature miRNAs involved in cell differentiation and Hox gene control; a bipartite sequence motif in the miRNA is necessary and sufficient for Zcchc6/11-catalyzed uridylation; TUTase depletion leads to loss of 3' mono-uridylation and a concomitant increase in non-templated 3' mono-adenylation.\",\n      \"method\": \"In vitro uridylation assays, biochemical motif definition, siRNA knockdown in cultured cells with deep sequencing, zebrafish developmental perturbation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemistry defining sequence motif, orthogonal cell-based knockdown and sequencing, plus in vivo zebrafish validation\",\n      \"pmids\": [\"25223788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TUT7 uses three mechanistically distinct uridylation modes for pre-miRNAs depending on 3'-overhang structure: (1) mono-uridylation of group II pre-miRNAs (1-nt 3' overhang) to restore canonical 2-nt overhang and promote biogenesis; (2) oligo-uridylation of 3'-trimmed (recessed) pre-miRNAs to mark them for degradation; (3) in the absence of Lin28, both modes are distributive (not processive), and overhang length dictates frequency—but not duration—of TUT7-RNA interaction.\",\n      \"method\": \"Biochemistry (in vitro uridylation assays), single-molecule experiments, deep sequencing\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (in vitro biochemistry, single-molecule, deep sequencing) in one rigorous study\",\n      \"pmids\": [\"25979828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TUT7 is the primary TUTase responsible for oligouridylation at the 3' end of histone mRNAs and of degradation intermediates within the stem-loop during histone mRNA degradation; TUT7 and 3'hExo function together in trimming and uridylating histone mRNAs. Knockdown of TUT4 did not alter the uridylation pattern at the 3' end.\",\n      \"method\": \"siRNA knockdown of TUT7 and TUT4 followed by high-throughput sequencing of histone mRNAs and degradation intermediates\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with deep sequencing readout, single lab, but two enzymes compared\",\n      \"pmids\": [\"27609902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TUT4 and TUT7 utilize two multidomain functional modules to switch between mono-uridylation (promoting let-7 expression) and oligo-uridylation (marking for degradation): a catalytic module (CM) essential for both activities and a Lin28-interacting module (LIM) indispensable for oligo-uridylation. A crystal structure of the TUT7 CM in the mono-uridylation state reveals a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins to favor monoU addition. The ZK domain of Lin28 drives formation of a stable ternary complex with pre-let-7 and the inactive LIM, and ZK2 of TUT4/7 engages the growing oligoU tail through uracil-specific interactions.\",\n      \"method\": \"Crystal structure determination of TUT7 CM, domain deletion/mutagenesis, in vitro uridylation assays, biochemical complex reconstitution\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus reconstitution and mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28671666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zcchc6 (TUT7) is expressed in mouse and human primary macrophages; Zcchc6-deficient macrophages exhibit increased expression of select cytokines (IL-6, CXCL1, CXCL5) following bacterial (S. pneumoniae) stimulation, indicating TUT7 has a suppressive role in macrophage innate immune cytokine responses.\",\n      \"method\": \"Zcchc6 knockout mouse generation, intratracheal bacterial challenge, in vitro macrophage stimulation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, single lab\",\n      \"pmids\": [\"28665939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZCCHC6 (TUT7) enhances IL-6 expression in chondrocytes by (1) stabilizing the IL-6 transcript and (2) uridylating miR-26b, which abrogates miR-26b-mediated repression of IL-6. Zcchc6 knockout mice with surgically induced osteoarthritis show reduced IL-6 levels and reduced cartilage damage.\",\n      \"method\": \"siRNA knockdown and overexpression in human chondrocytes, actinomycin D chase for mRNA stability, deep sequencing for miRNA 3'-uridylation, Zcchc6 knockout mouse model with surgical OA induction, Zcchc6 rescue in KO chondrocytes\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, overexpression, KO mouse, mRNA stability assay, deep sequencing, rescue), single lab but comprehensive\",\n      \"pmids\": [\"30302948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TUT7 knockout in HEK293T cells reveals that TUT4 uridylates most miRNAs whereas TUT7 alone is dispensable for bulk miRNA uridylation; however, specific miRNAs (miR-888 cluster) are upregulated specifically by TUT7, indicating selective substrate control. Abolishing uridylation (TUT4/7 double KO) dysregulates a defined set of miRNAs including let-7, miR-181b, and miR-222.\",\n      \"method\": \"CRISPR knockout of TENT2, TUT4, TUT7 individually and in combination in isogenic HEK293T lines, deep sequencing, Northern blot, in vitro assays, rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — isogenic CRISPR KO lines with multiple orthogonal methods and rescue experiments\",\n      \"pmids\": [\"36071058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TUT7 (TENT3B/ZCCHC6) specifically uridylates histone mRNA degradation intermediates in the stem-loop region; knockout of TUT7 prevents uridylation of these intermediates and slows the rate of histone mRNA degradation without blocking initiation. TUT7 and 3'hExo cooperate: 3'hExo initiates degradation and maintains histone mRNA 3'-end length while TUT7 uridylates intermediates to facilitate complete degradation.\",\n      \"method\": \"TUT7 and 3'hExo CRISPR knockout in human cells, cell synchronization, high-throughput sequencing of histone mRNA degradation intermediates\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KOs with deep sequencing and cell synchronization, replicates and extends earlier knockdown findings\",\n      \"pmids\": [\"36041871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TUT7 functions as a salvage RNA decay mechanism in FOCAD-deleted cancer cells: FOCAD loss destabilizes the SKI complex, and TUT7 (together with DIS3L2) then degrades aberrant RNA; genetic or pharmacologic inhibition of TUT7 selectively kills FOCAD-deleted cancer cells. TUT7 knockout (but not TUT4 knockout) impairs proliferation in FOCAD-loss cancer cells, indicating non-redundant roles.\",\n      \"method\": \"CRISPR knockout of TUT7, TUT4, DIS3L2, and FOCAD; functional genomics data analysis; first potent/selective TUT4/7 small-molecule inhibitors with in vitro and in vivo antiproliferative assays; FOCAD reintroduction rescue experiment\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO epistasis, pharmacological inhibitors, in vivo data, and genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39235218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TUT7-mediated uridylation of mature miR-1246 promotes its degradation as a small noncoding RNA (not from the precursor miR-1246), and this process is stabilized by SNRPB; this leads to accumulation of exosomal miR-1246 in colorectal cancer, which drives TAM polarization and CD8+ T cell suppression.\",\n      \"method\": \"Co-culture macrophage education system, TUT7 functional characterization, database mining validated by in vitro experiments, RNA-seq\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism described at abstract level without detailed in vitro reconstitution; abstract is not fully explicit about TUT7-specific assays\",\n      \"pmids\": [\"38342611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUT7 (and TUT4) uridylate the 5' cleavage fragment generated by KHNYN endonuclease cleavage of viral RNA during ZAP-mediated RNA decay (ZMD); the uridylated fragment is then degraded by DIS3L2. TUT7 interacts with ZAP and TRIM25 in a RNase-resistant manner, and viral infection promotes TRIM25 interaction with TUT7.\",\n      \"method\": \"RNase-resistant co-immunoprecipitation, ordered pathway dissection, overexpression and interaction studies in ZMD pathway reconstitution (preprint)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pathway reconstitution with ordered epistasis, single preprint study\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.650959\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUT7 reduces the stability of MCPIP1 mRNA through uridylation (demonstrated by in vitro transcription and uridylation experiments), thereby weakening MCPIP1-mediated suppression of pterygium fibroblast autophagy and fibrosis.\",\n      \"method\": \"In vitro transcription and uridylation assays, co-immunoprecipitation, Western blot, qRT-PCR, immunohistochemistry, transwell migration and wound-healing assays, immunofluorescence\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro uridylation assay plus multiple cellular assays, single lab\",\n      \"pmids\": [\"40238115\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TUT7 (ZCCHC6/ZCCHC11 paralog) is a terminal uridylyl transferase that operates via three mechanistically distinct modes—Lin28-stimulated processive oligo-uridylation to suppress let-7 biogenesis, distributive mono-uridylation to repair group II pre-miRNAs, and oligo-uridylation of trimmed pre-miRNAs or mRNA degradation intermediates to promote their decay—and its catalytic module (structurally resolved) plus a Lin28-interacting module govern switching between these activities; beyond miRNA regulation, TUT7 is the primary TUTase for uridylating histone mRNA 3' ends and degradation intermediates in cooperation with 3'hExo, it uridylates specific mature miRNAs (including miR-26b and miR-1246) to modulate inflammatory gene expression, it acts as a salvage RNA decay enzyme for aberrant transcripts in FOCAD-deficient cells together with DIS3L2, and it is recruited by the ZAP/TRIM25 complex to uridylate viral RNA fragments for antiviral defense.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TUT7 (ZCCHC6/TENT3B) is a terminal uridylyl transferase that controls RNA fate by adding non-templated uridines to the 3' ends of small RNAs, mRNAs, and decay intermediates, acting redundantly with or independently of its paralog TUT4 depending on substrate [#0, #7]. In let-7 biogenesis it operates through two structurally and kinetically distinct modes dictated by pre-miRNA 3'-overhang structure: distributive mono-uridylation of group II pre-miRNAs restores a canonical 2-nucleotide overhang to promote maturation, while oligo-uridylation of 3'-trimmed precursors marks them for degradation [#2]. Mode switching is governed by two functional modules\\u2014a catalytic module whose crystal structure reveals a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins for mono-U addition, and a Lin28-interacting module that, engaged by the Lin28 ZK domain, forms a stable ternary complex enabling processive oligo-uridylation [#4]. TUT7 also recognizes a bipartite sequence motif to mono-uridylate a specific subset of mature miRNAs, with depletion shifting the 3' end toward mono-adenylation [#1]. Beyond miRNA control, TUT7 is the primary TUTase uridylating histone mRNA 3' ends and stem-loop degradation intermediates in cooperation with the 3'\\u21925' exonuclease 3'hExo to drive complete histone mRNA decay [#3, #8], and it serves as a salvage decay enzyme acting with DIS3L2 to clear aberrant transcripts in FOCAD-deficient cells, where its loss is selectively lethal [#9]. Through targeted uridylation of specific mature miRNAs (miR-26b) and mRNAs (IL-6), TUT7 modulates inflammatory and tissue-remodeling gene expression and contributes to phenotypes including osteoarthritic cartilage damage [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that TUT7 is a bona fide uridylyl transferase that, like TUT4, interacts with Lin28 to uridylate pre-let-7 and that the two enzymes redundantly control let-7 biogenesis, defining TUT7's founding role in the Lin28/let-7 axis.\",\n      \"evidence\": \"In vitro uridylation and reconstitution assays, domain-deletion mapping of a C2H2 zinc finger, and ES cell depletion\",\n      \"pmids\": [\"22898984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of catalysis or substrate discrimination\", \"Degree of substrate-specific division of labor between TUT4 and TUT7 left open\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed TUT7/TUT4 selectively mono-uridylate a defined subset of mature miRNAs via a bipartite sequence motif, revealing sequence-specific substrate recognition and an antagonism with 3' adenylation.\",\n      \"evidence\": \"In vitro motif-definition biochemistry, siRNA knockdown with deep sequencing, and zebrafish developmental perturbation\",\n      \"pmids\": [\"25223788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the motif is read structurally\", \"Functional consequences of mono-U vs mono-A on individual miRNAs not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the mechanistic logic of TUT7 mode-switching, showing 3'-overhang structure dictates mono- versus oligo-uridylation and that, absent Lin28, both modes are distributive with overhang length controlling interaction frequency.\",\n      \"evidence\": \"In vitro uridylation assays, single-molecule experiments, and deep sequencing\",\n      \"pmids\": [\"25979828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for overhang discrimination not yet visualized\", \"How Lin28 converts distributive to processive activity left for later work\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TUT7 as the primary TUTase uridylating histone mRNA 3' ends and stem-loop degradation intermediates, distinguishing it functionally from TUT4 and linking it to histone mRNA turnover with 3'hExo.\",\n      \"evidence\": \"siRNA knockdown of TUT7 and TUT4 with high-throughput sequencing of histone mRNAs\",\n      \"pmids\": [\"27609902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown rather than knockout; residual enzyme possible\", \"Direct physical cooperation with 3'hExo not biochemically reconstituted here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the modular and structural basis of TUT7 activity by solving the catalytic module crystal structure in the mono-uridylation state and mapping a Lin28-interacting module required specifically for oligo-uridylation, explaining mode switching at atomic resolution.\",\n      \"evidence\": \"Crystal structure of the TUT7 catalytic module, domain mutagenesis, in vitro assays, and ternary complex reconstitution\",\n      \"pmids\": [\"28671666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure including the LIM in the active oligo-U state\", \"Structural transitions during processive synthesis not captured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TUT7 to innate immunity, showing macrophage TUT7 suppresses select cytokine responses to bacterial challenge, extending its role beyond RNA biogenesis into immune regulation.\",\n      \"evidence\": \"Zcchc6 knockout mice, intratracheal bacterial challenge, and macrophage stimulation assays\",\n      \"pmids\": [\"28665939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA substrate(s) mediating the cytokine phenotype not identified\", \"Catalytic dependence of the immune effect not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a dual mechanism by which TUT7 amplifies IL-6 expression\\u2014stabilizing the IL-6 transcript and uridylating miR-26b to relieve its repression of IL-6\\u2014and linked this to osteoarthritis pathology in vivo.\",\n      \"evidence\": \"Chondrocyte knockdown/overexpression, actinomycin D mRNA-stability chase, miRNA uridylation sequencing, and a surgical osteoarthritis KO mouse model with rescue\",\n      \"pmids\": [\"30302948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which miR-26b uridylation abrogates repression not detailed\", \"Generality of TUT7-mediated mRNA stabilization beyond IL-6 unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Using isogenic CRISPR knockouts, established the division of labor between TUT4 and TUT7\\u2014TUT4 drives bulk miRNA uridylation while TUT7 selectively controls specific miRNAs (miR-888 cluster)\\u2014and defined a uridylation-dependent miRNA set including let-7, miR-181b, and miR-222.\",\n      \"evidence\": \"CRISPR knockout of TENT2/TUT4/TUT7 alone and combined, deep sequencing, Northern blot, in vitro assays, and rescue\",\n      \"pmids\": [\"36071058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for TUT7's selectivity toward specific miRNAs not mechanistically explained\", \"Functional consequences for each dysregulated miRNA not all defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed via knockout that TUT7 uridylation of histone mRNA stem-loop degradation intermediates accelerates complete decay and that TUT7 cooperates with 3'hExo, which initiates trimming and sets 3'-end length.\",\n      \"evidence\": \"CRISPR knockout of TUT7 and 3'hExo, cell synchronization, and deep sequencing of degradation intermediates\",\n      \"pmids\": [\"36041871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction and ordering of TUT7/3'hExo not structurally resolved\", \"Downstream nuclease completing decay of uridylated intermediates not defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a synthetic-lethal salvage RNA decay role in which FOCAD loss destabilizes the SKI complex and makes cells dependent on TUT7 (with DIS3L2) to clear aberrant RNA, nominating TUT7 as a selective cancer target and yielding first-in-class TUT4/7 inhibitors.\",\n      \"evidence\": \"CRISPR knockout epistasis (TUT7/TUT4/DIS3L2/FOCAD), functional genomics, FOCAD-reintroduction rescue, and small-molecule inhibitors with in vivo antiproliferative assays\",\n      \"pmids\": [\"39235218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the aberrant transcripts salvaged by TUT7 not enumerated\", \"Mechanism rendering TUT7 non-redundant with TUT4 in this context unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed that TUT7 uridylates mature miR-1246 to promote its turnover, with SNRPB stabilization shaping exosomal miR-1246 levels that drive tumor-associated macrophage polarization and T cell suppression in colorectal cancer.\",\n      \"evidence\": \"Macrophage co-culture education system, TUT7 functional characterization, RNA-seq, and database mining\",\n      \"pmids\": [\"38342611\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism described at abstract level without detailed TUT7-specific in vitro reconstitution\", \"Direct enzymatic action on mature miR-1246 not biochemically isolated\", \"SNRPB\\u2013TUT7 relationship not mechanistically defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed TUT7 within antiviral ZAP-mediated RNA decay, showing it uridylates the 5' KHNYN-cleavage fragment of viral RNA for DIS3L2 degradation and physically associates with ZAP and TRIM25 in an infection-enhanced, RNase-resistant manner.\",\n      \"evidence\": \"RNase-resistant co-immunoprecipitation, ordered pathway dissection, and ZMD reconstitution (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.650959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Structural basis of ZAP/TRIM25\\u2013TUT7 recruitment unresolved\", \"Relative contributions of TUT4 vs TUT7 in ZMD not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TUT7's mRNA-destabilizing activity to MCPIP1, showing uridylation lowers MCPIP1 transcript stability and thereby modulates autophagy and fibrosis in pterygium fibroblasts.\",\n      \"evidence\": \"In vitro transcription/uridylation assays, co-IP, Western blot, qRT-PCR, and cellular migration/wound-healing assays\",\n      \"pmids\": [\"40238115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study in a specialized cell context\", \"Generality of TUT7-mediated mRNA destabilization across tissues unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TUT7 achieves substrate selectivity across its diverse RNA targets\\u2014miRNAs, histone mRNAs, mRNAs, and viral fragments\\u2014and what determines its non-redundant versus redundant relationship with TUT4 in each pathway remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model explaining differential substrate engagement\", \"Cofactors/adaptors directing TUT7 to specific decay vs biogenesis pathways largely unmapped\", \"Full-length enzyme structure in oligo-uridylation state lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LIN28\", \"3'hExo\", \"DIS3L2\", \"ZAP\", \"TRIM25\", \"SNRPB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}