{"gene":"TENT5C","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2017,"finding":"FAM46C/TENT5C encodes an active non-canonical poly(A) polymerase; catalytically-inactive mutant fails to enhance mRNA stability or induce cell death, establishing that enzymatic activity is required for its tumor-suppressive function in multiple myeloma.","method":"In vitro poly(A) polymerase assay, catalytic mutant re-introduction into MM cell lines, mRNA stability assays, Nanopore direct RNA-sequencing of poly(A) tails","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with catalytic mutant, replicated across multiple cell lines and in vivo KO mouse model, multiple orthogonal methods","pmids":["28931820"],"is_preprint":false},{"year":2020,"finding":"TENT5C polyadenylates immunoglobulin mRNAs in activated B cells, regulating their half-life and steady-state levels; catalytic activity knock-in mice display the same impaired antibody production phenotype as Tent5c-/- mice, confirming enzymatic activity is required.","method":"Nanopore direct RNA-sequencing for poly(A) tail length distribution, catalytic mutation knock-in mice, Tent5c-/- mouse model with immune response measurements, poly(A) tail-length assays on Ig mRNAs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — poly(A) tail profiling with direct RNA-seq, catalytic knock-in mice, KO mice with defined immune phenotype, multiple orthogonal methods in single study","pmids":["32341344"],"is_preprint":false},{"year":2020,"finding":"FAM46C selectively stabilizes mRNAs encoding ER-targeted proteins (ER protein import, folding, N-glycosylation, trafficking) and requires interaction with ER membrane resident proteins FNDC3A and FNDC3B for this activity; FAM46C activity is regulated by proteasomal degradation or inhibitory interaction with the ZZ domain of autophagic receptor p62, which sequesters it in p62+ aggregates and prevents its association with FNDC3 proteins.","method":"Co-immunoprecipitation, biochemical fractionation, mRNA stability assays, proteasome inhibition experiments, p62 ZZ-domain binding assay, MS-based proteomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple interaction partners validated, functional consequences of complex disruption measured, single lab with multiple orthogonal methods","pmids":["32966780"],"is_preprint":false},{"year":2020,"finding":"FAM46C forms a complex with ER-associated protein FNDC3A; this complex requires FNDC3A for FAM46C to reside on the cytoplasmic side of the ER. The FAM46C/FNDC3A complex modulates secretion routes and impairs autophagy, leading to accumulation of intracellular protein aggregates and apoptosis in MM cells.","method":"Biochemical analysis/Co-IP, reconstitution of FAM46C in MM cells that lost it, FNDC3A depletion and expression rescue experiments, autophagy assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis via FNDC3A rescue experiment, multiple cell lines tested, replicated functional effects across independent labs (corroborates PMID 32966780)","pmids":["32963011"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of mammalian FAM46C at 2.35 Å reveals it is a prokaryotic-like poly(A) polymerase that preferentially uses ATP and extends A-rich RNA substrates; residues at positions 77, 290, and 298 are key determinants of enzymatic activity divergence from homolog FAM46B; MM-associated mutations at the catalytic site (D90G, D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, M270V) abolish or compromise PAP activity and anti-apoptotic suppression.","method":"X-ray crystallography (2.35 Å), site-directed mutagenesis, in vitro poly(A) polymerase biochemical assays, cell-based apoptosis assay with mutant variants","journal":"Cancer communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus site-directed mutagenesis plus in vitro enzymatic assays in one study, multiple mutants systematically tested","pmids":["34048638"],"is_preprint":false},{"year":2020,"finding":"FAM46C physically interacts with the serine/threonine kinase Plk4; crystal structure of FAM46C in complex with the Cryptic Polo-Box 1-2 (CPB1-2) domains of Plk4 was determined; this interaction recruits FAM46C to centrosomes; FAM46C inhibits Plk4 kinase activity and suppresses Plk4-induced centriole duplication independently of FAM46C's nucleotidyl transferase activity.","method":"Crystal structure of FAM46C-Plk4 CPB1-2 complex, structure-based mutational analyses, Co-IP, kinase activity assay, centriole duplication assay, xenograft model","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure with structure-based mutagenesis, kinase assay, functional centriole duplication assay in one study","pmids":["32433990"],"is_preprint":false},{"year":2020,"finding":"FAM46C/TENT5C localizes to centrioles and inhibits Plk4 kinase activity, suppressing centriole overduplication and cancer cell invasion; this function is independent of its nucleotidyltransferase activity; FAM46C loss is detected in patient-derived colorectal cancer tissue correlating with advanced clinical stage.","method":"Co-IP (physical interaction with Plk4), immunofluorescence localization to centrioles, Plk4 kinase inhibition assay, centriole counting, invasion assay, xenograft model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase assay, live-cell imaging localization with functional consequence, xenograft validation, multiple orthogonal methods","pmids":["32807875"],"is_preprint":false},{"year":2019,"finding":"FAM46C localizes specifically to the manchette (a transient microtubule-based structure) of spermatids in mouse testes; FAM46C knockout causes male sterility with headless spermatozoa; FAM46C does not exhibit protein kinase or AMPylation activity against general substrates in vitro.","method":"Immunofluorescence localization, gene knockout mouse model, intracytoplasmic sperm injection assay, RNA-seq of KO testes, in vitro kinase and AMPylation activity assays (negative for both)","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct immunolocalization, KO mouse with specific fertility phenotype, in vitro activity assays with negative controls","pmids":["31087039"],"is_preprint":false},{"year":2026,"finding":"TENT5C poly(A) polymerase activity is required to extend poly(A) tails of Odf1 mRNA in late spermatids; absence of TENT5C catalytic activity causes shorter Odf1 poly(A) tails, failure of ODF1 protein accumulation at the spermatid neck, and production of headless spermatozoa with flagellar abnormalities, establishing Odf1 as a direct in vivo substrate critical for sperm morphogenesis.","method":"Catalytically-inactive TENT5C knock-in mice, transcriptome-wide poly(A) tail profiling, immunofluorescence for ODF1 localization, sperm morphology analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic knock-in mouse with poly(A) tail profiling and protein localization, identifying specific mRNA substrate with functional consequence, peer-reviewed","pmids":["42009655"],"is_preprint":false},{"year":2020,"finding":"FAM46C polyadenylates immunoglobulin heavy and light chain mRNAs as direct substrates in plasma cells; FAM46C inactivation (CRISPR-Cas9) causes poly(A) tail shortening of Ig mRNAs, reducing their abundance and protein output; loss of FAM46C also upregulates MALAT1 lncRNA and activates PI3K/Rac1 signaling to increase myeloma cell migration.","method":"CRISPR-Cas9 FAM46C inactivation, poly(A) tail-length determination assays on Ig mRNAs, gene expression analysis, migration assay with PI3K/Rac1 pathway inhibitors","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct poly(A) tail measurement on specific substrates with CRISPR KO, functional migration assay, single lab","pmids":["32141701"],"is_preprint":false},{"year":2017,"finding":"Wild-type FAM46C overexpression in MM cells downregulates IRF4, CEBPB, and MYC while upregulating immunoglobulin light chain and HSPA5/BIP; CRISPR-mediated depletion of endogenous FAM46C activates ERK and antiapoptotic signaling and confers resistance to dexamethasone and lenalidomide; myeloma mutations in FAM46C abrogate its cytotoxicity.","method":"FAM46C overexpression with patient-derived mutants, CRISPR KO in MM cell lines, gene expression analysis, drug sensitivity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO and OE with defined molecular endpoints, multiple MM cell lines, single lab","pmids":["28619709"],"is_preprint":false},{"year":2020,"finding":"Loss of FAM46C in MM cells triggers activation of PI3K-Akt signaling, decreasing PTEN activity and increasing phosphorylation of Akt and its substrates both in vitro and in vivo; a selective PI3K inhibitor (PF-04691502) or Akt inhibitor (afuresertib) suppresses the augmented Akt phosphorylation in FAM46C-/- cells.","method":"CRISPR-generated FAM46C-/- MM cell clones, xenograft mouse model, western blotting for p-Akt and substrates, PTEN activity assay, PI3K/Akt inhibitor treatment, gene set enrichment analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with in vivo validation, biochemical Akt/PTEN measurements, single lab with multiple orthogonal methods","pmids":["32176823"],"is_preprint":false},{"year":2023,"finding":"FAM46C is an interferon-stimulated gene; wild-type FAM46C expression in HEK-293T cells inhibits production of HIV-1-derived and HIV-1 lentiviruses through deregulation of autophagy (a pathway required for efficient lentiviral particle production), not through transcriptional or translational inhibition; frequent MM-associated mutant variants of FAM46C do not inhibit lentiviral production.","method":"Interferon stimulation assays, lentiviral production assays with WT vs. mutant FAM46C overexpression, autophagy perturbation experiments, translation inhibition controls","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional lentiviral production assay with WT vs. mutant FAM46C, autophagy mechanism dissected, single lab","pmids":["37358411"],"is_preprint":false},{"year":2025,"finding":"TENT5C acts as a corepressor of both glucocorticoid receptor (GR) and estrogen receptor α (ERα); the third LXXLL motif of TENT5C directly interacts with ERα (supported by molecular dynamics simulations and Co-IP); mutation of the third LXXLL motif disrupts repression of ERα but not GR; TENT5C poly(A) polymerase activity is not required for repression of ERα.","method":"Co-immunoprecipitation (TENT5C with ERα), reporter assays (GR and ERα transcriptional activity), LXXLL motif mutagenesis, molecular dynamics simulations, catalytic mutant controls","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and reporter assays, multiple orthogonal methods, single lab","pmids":["40421654"],"is_preprint":false},{"year":2024,"finding":"FAM46C is required for proper erythropoiesis; it stabilizes mRNA in a polymerase activity-dependent manner during red blood cell development; direct in vivo targets include transcripts encoding lysosome and mitochondria components, consistent with the need for organelle clearance during erythroid maturation; FAM46C upregulation in late erythroid stages is controlled by an erythroid-specific enhancer.","method":"FAM46C KO in erythroid cells, mRNA stability assays, erythroid differentiation assays, enhancer characterization, transcriptome analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with mRNA stability assays and defined cellular phenotype, enhancer experiment, single lab","pmids":["38403115"],"is_preprint":false},{"year":2024,"finding":"TENT5C cooperates with LARP4/5 RNA-binding proteins to maintain globin mRNA poly(A) tails and hemoglobin production during terminal erythropoiesis; TENT5C catalytic mutant knock-in mice display microcytic hypochromic anemia; proteomics revealed a transient but specific association of TENT5C with LARP4/5; LARP4/5 depletion causes poly(A) tail shortening and downregulation of globin mRNAs; TENT5C is destabilized by CCR4-NOT-associated E3 ubiquitin ligase CNOT4.","method":"Catalytic mutant knock-in mice, poly(A) tail profiling, proteomic Co-IP (TENT5C-LARP4/5), LARP4/5 depletion, CNOT4-mediated ubiquitination/degradation assay","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic knock-in mice with phenotype, proteomic Co-IP, poly(A) profiling, multiple orthogonal methods; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2020,"finding":"FAM46C overexpression in HCC cells suppresses cell migration and invasion by suppressing TGF-β/Smad signaling and inhibiting epithelial-mesenchymal transition (EMT); antimetastatic effects of NCTD on HCC cells are partially rescued by FAM46C knockdown.","method":"FAM46C overexpression and knockdown in HCC cell lines, migration/invasion assays, western blotting for TGF-β/Smad pathway components and EMT markers","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway western blots with OE/KD, no direct mechanistic link established between FAM46C poly(A) activity and TGF-β/Smad","pmids":["28123642"],"is_preprint":false},{"year":2020,"finding":"FAM46C promotes PTEN expression in prostate cancer cells by inhibiting PTEN ubiquitination, thereby suppressing AKT activation; FAM46C KD activates AKT and promotes cell proliferation.","method":"FAM46C knockdown and overexpression in prostate cancer cell lines, PTEN ubiquitination assay, AKT phosphorylation western blot, in vivo tumor growth assay","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ubiquitination assay without identification of specific E3 ligase or direct mechanistic connection to FAM46C PAP activity","pmids":["32283544"],"is_preprint":false},{"year":2024,"finding":"TENT5C expression is regulated by DNMT3A-mediated gene body methylation; DNMT3A knockdown increases enrichment of DNMT3B and DNMT1 at the FAM46C gene body, elevating FAM46C transcription; elevated FAM46C suppresses trophoblast cell migration and invasion.","method":"Bisulfite sequencing of FAM46C gene body, DNMT3A siRNA knockdown, ChIP or methylation enrichment analysis, RNA-seq, migration/invasion rescue experiments","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect regulation mechanism, functional rescue experiments but no direct mechanistic link to FAM46C protein activity","pmids":["39532219"],"is_preprint":false},{"year":2024,"finding":"TENT5C downregulation mediates the anti-inflammatory effects of mild hypothermia in LPS-stimulated microglia; TENT5C knockdown attenuates expression of pro-inflammatory genes (TNF-α, IL-1β, Agrn, Fpr2), NLRP3 and p-P65 levels, and ASC-speck formation; TENT5C overexpression potentiates these inflammatory indicators.","method":"siRNA knockdown of Tent5c in BV-2 microglial cells, LPS stimulation, RT-PCR, western blot for NLRP3 and p-P65, immunofluorescence for p-P65 and ASC-speck","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/OE with defined inflammatory phenotype but no direct molecular mechanism linking TENT5C poly(A) activity to NF-κB/NLRP3 pathway","pmids":["38484570"],"is_preprint":false}],"current_model":"TENT5C/FAM46C is a cytoplasmic non-canonical poly(A) polymerase that stabilizes specific mRNA subsets — including immunoglobulin mRNAs in plasma cells, ER-targeted protein mRNAs in secretory cells, globin mRNAs in erythroid cells, and Odf1 mRNA in spermatids — through its catalytic activity, with its enzymatic activity proven required for all major physiological functions; in addition to its RNA-regulatory role, TENT5C physically interacts with FNDC3A/B at the ER to modulate secretory trafficking and autophagy, with the autophagic receptor p62 sequestering TENT5C via its ZZ domain to limit its activity, and TENT5C also localizes to centrioles by binding the CPB1-2 domains of Plk4 to inhibit Plk4 kinase activity and suppress centriole duplication independently of its nucleotidyl transferase activity, while also acting as a corepressor of glucocorticoid and estrogen receptors via an LXXLL motif-dependent mechanism."},"narrative":{"mechanistic_narrative":"TENT5C (FAM46C) is a cytoplasmic non-canonical poly(A) polymerase that stabilizes defined mRNA subsets by extending their poly(A) tails, a function central to its role as a tumor suppressor in multiple myeloma and to terminal differentiation programs in secretory, erythroid, and germ cells [PMID:28931820, PMID:32341344]. Structurally it is a prokaryotic-like poly(A) polymerase that preferentially uses ATP to extend A-rich substrates, and myeloma-associated mutations at its catalytic or RNA-binding residues abolish polymerase activity and its pro-apoptotic suppression of malignant cells [PMID:34048638]. Its catalytic activity is required across physiological contexts: it polyadenylates immunoglobulin heavy and light chain mRNAs in plasma cells to sustain antibody output [PMID:32341344, PMID:32141701], stabilizes ER-targeted protein mRNAs in secretory cells through interaction with the ER membrane proteins FNDC3A/FNDC3B, which tether it to the cytoplasmic face of the ER and couple it to secretory routing and autophagy [PMID:32966780, PMID:32963011], and extends the poly(A) tail of Odf1 mRNA in spermatids to drive sperm head morphogenesis [PMID:42009655]. During terminal erythropoiesis it maintains globin mRNA poly(A) tails in cooperation with the LARP4/5 RNA-binding proteins and stabilizes transcripts encoding organelle-clearance machinery [PMID:38403115]. TENT5C activity is restrained by post-translational and sequestration mechanisms, including proteasomal degradation, CNOT4-mediated ubiquitination, and capture by the autophagy receptor p62 via its ZZ domain [PMID:32966780]. Independently of its enzymatic activity, TENT5C localizes to centrioles by binding the CPB1-2 domains of Plk4, inhibiting Plk4 kinase activity to suppress centriole overduplication and invasion [PMID:32433990, PMID:32807875], and acts as a corepressor of glucocorticoid and estrogen receptor α through an LXXLL-motif-dependent interaction [PMID:40421654].","teleology":[{"year":2017,"claim":"Established that TENT5C is an enzyme rather than a passive scaffold, defining its non-canonical poly(A) polymerase activity as the basis of its tumor-suppressive cell-death function in myeloma.","evidence":"In vitro poly(A) polymerase assay with catalytically-inactive mutant re-introduction into MM lines, mRNA stability assays, and Nanopore direct RNA-seq of poly(A) tails","pmids":["28931820"],"confidence":"High","gaps":["Did not identify the specific endogenous mRNA substrates","Mechanism coupling tail extension to cell death not resolved"]},{"year":2017,"claim":"Linked TENT5C function to downstream transcriptional programs and drug sensitivity, showing its loss activates survival signaling and confers resistance to myeloma therapeutics.","evidence":"FAM46C overexpression with patient-derived mutants and CRISPR KO in MM cell lines, gene expression analysis, drug sensitivity assays","pmids":["28619709"],"confidence":"Medium","gaps":["IRF4/MYC/CEBPB changes not tied directly to poly(A) activity","ERK activation mechanism downstream of loss unresolved"]},{"year":2019,"claim":"Identified a germ-cell role by localizing TENT5C to the spermatid manchette and showing knockout causes headless-sperm sterility, while ruling out kinase and AMPylation activities.","evidence":"Immunofluorescence, KO mouse model, ICSI assay, and negative in vitro kinase/AMPylation assays","pmids":["31087039"],"confidence":"High","gaps":["Did not identify the molecular substrate driving the phenotype","Did not establish whether poly(A) activity underlies sterility"]},{"year":2020,"claim":"Demonstrated immunoglobulin mRNAs are direct physiological substrates, with catalytic knock-in mice phenocopying knockouts to prove enzymatic activity drives antibody production.","evidence":"Nanopore direct RNA-seq poly(A) profiling, catalytic knock-in and Tent5c-/- mice with immune phenotyping; corroborated by CRISPR-KO poly(A) tail measurement on Ig mRNAs in plasma cells","pmids":["32341344","32141701"],"confidence":"High","gaps":["Substrate selection mechanism for Ig mRNAs not defined","MALAT1/PI3K-Rac1 migration link is indirect"]},{"year":2020,"claim":"Defined a spatial and regulatory framework for TENT5C's RNA activity, placing it on the cytoplasmic face of the ER via FNDC3A/B to stabilize secretory mRNAs and modulate trafficking and autophagy, with p62 ZZ-domain sequestration and proteasomal turnover as restraints.","evidence":"Reciprocal Co-IP, biochemical fractionation, FNDC3A depletion/rescue, p62 ZZ-domain binding assay, mRNA stability and autophagy assays across two independent labs","pmids":["32966780","32963011"],"confidence":"High","gaps":["How FNDC3 tethering selects ER-targeted mRNA substrates is unclear","Quantitative balance between RNA stabilization and aggregate-induced apoptosis not resolved"]},{"year":2020,"claim":"Revealed an enzymatic-activity-independent function at the centriole, showing TENT5C binds the Plk4 CPB1-2 domains to inhibit Plk4 kinase and suppress centriole overduplication and invasion.","evidence":"Co-crystal structure of FAM46C-Plk4 CPB1-2, structure-based mutagenesis, Co-IP, kinase and centriole-duplication assays, xenograft; corroborated by IF localization and invasion assays","pmids":["32433990","32807875"],"confidence":"High","gaps":["How the centriolar pool is partitioned from the cytoplasmic RNA-regulatory pool is unknown","In vivo contribution of Plk4 inhibition to tumor suppression not quantified"]},{"year":2020,"claim":"Connected TENT5C loss to a defined survival pathway in myeloma by showing it stabilizes PTEN function and its absence drives PI3K-Akt activation reversible by pathway inhibitors.","evidence":"CRISPR FAM46C-/- clones, xenograft, p-Akt/PTEN biochemistry, PI3K/Akt inhibitor treatment, GSEA","pmids":["32176823"],"confidence":"Medium","gaps":["Mechanistic link between poly(A) activity and PTEN/PI3K not established","Single-lab observation"]},{"year":2021,"claim":"Provided the structural basis for catalysis, defining TENT5C as a prokaryotic-like ATP-preferring poly(A) polymerase and mapping how disease mutations disable activity.","evidence":"2.35 Å X-ray crystal structure, site-directed mutagenesis, in vitro PAP assays, cell-based apoptosis assays with mutants","pmids":["34048638"],"confidence":"High","gaps":["Structure of an RNA-bound or partner-bound complex not solved","Determinants of in vivo substrate specificity not addressed"]},{"year":2024,"claim":"Extended the substrate-stabilization paradigm to erythropoiesis, showing TENT5C maintains globin mRNA poly(A) tails with LARP4/5 cofactors and stabilizes organelle-clearance transcripts under enhancer control.","evidence":"Erythroid KO, mRNA stability and differentiation assays, enhancer characterization, transcriptomics; preprint catalytic knock-in mice with anemia, LARP4/5 proteomic Co-IP, and CNOT4 degradation assay","pmids":["38403115"],"confidence":"Medium","gaps":["LARP4/5 cooperation evidence is from a preprint not yet peer-reviewed","How CNOT4 turnover is timed during differentiation is unclear"]},{"year":2025,"claim":"Uncovered a non-RNA nuclear-receptor function, identifying TENT5C as an LXXLL-motif corepressor of GR and ERα independent of its polymerase activity.","evidence":"Co-IP with ERα, GR/ERα reporter assays, LXXLL mutagenesis, molecular dynamics, catalytic mutant controls","pmids":["40421654"],"confidence":"Medium","gaps":["Endogenous target genes of TENT5C-mediated repression not defined","Single-lab, partly simulation-supported interaction"]},{"year":2026,"claim":"Closed the germ-cell mechanism by identifying Odf1 mRNA as the direct in vivo substrate whose tail extension by TENT5C is required for sperm head assembly.","evidence":"Catalytic knock-in mice, transcriptome-wide poly(A) profiling, ODF1 immunofluorescence, sperm morphology analysis","pmids":["42009655"],"confidence":"High","gaps":["Whether additional spermatid substrates contribute to the phenotype not excluded","Recruitment of TENT5C to specific spermatid mRNAs not defined"]},{"year":null,"claim":"How TENT5C selects its tissue-specific mRNA substrates and how its three biochemical modes — cytoplasmic poly(A) polymerase, centriolar Plk4 inhibitor, and nuclear-receptor corepressor — are spatially and temporally partitioned within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate recognition across cell types","No structural or single-cell data resolving the multiple functional pools","Relationship between RNA-dependent and RNA-independent functions in tumor suppression unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,4,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,8,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4,10]}],"complexes":[],"partners":["FNDC3A","FNDC3B","PLK4","SQSTM1","LARP4","LARP5","CNOT4","ESR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VWP2","full_name":"Terminal nucleotidyltransferase 5C","aliases":["Non-canonical poly(A) polymerase FAM46C"],"length_aa":391,"mass_kda":44.9,"function":"Catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group and enhances mRNA stability and gene expression (PubMed:28931820, PubMed:32009146, PubMed:34048638). Can also elongate RNA oligos ending with uridine molecule, provided that the sequence is adenosine-rich (PubMed:34048638). Mainly targets mRNAs encoding endoplasmic reticulum-targeted protein (PubMed:28931820) (Microbial infection) Seems to enhance replication of some viruses, including yellow fever virus, in response to type I interferon","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q5VWP2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TENT5C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TENT5C","total_profiled":1310},"omim":[{"mim_id":"613952","title":"TERMINAL NUCLEOTIDYLTRANSFERASE 5C; TENT5C","url":"https://www.omim.org/entry/613952"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":84.0}],"url":"https://www.proteinatlas.org/search/TENT5C"},"hgnc":{"alias_symbol":["FLJ20202"],"prev_symbol":["FAM46C"]},"alphafold":{"accession":"Q5VWP2","domains":[{"cath_id":"-","chopping":"9-229","consensus_level":"medium","plddt":94.3665,"start":9,"end":229},{"cath_id":"1.20.1310","chopping":"234-349","consensus_level":"medium","plddt":90.2115,"start":234,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWP2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWP2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWP2-F1-predicted_aligned_error_v6.png","plddt_mean":87.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TENT5C","jax_strain_url":"https://www.jax.org/strain/search?query=TENT5C"},"sequence":{"accession":"Q5VWP2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VWP2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VWP2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWP2"}},"corpus_meta":[{"pmid":"21994415","id":"PMC_21994415","title":"Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21994415","citation_count":153,"is_preprint":false},{"pmid":"28931820","id":"PMC_28931820","title":"The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28931820","citation_count":84,"is_preprint":false},{"pmid":"32341344","id":"PMC_32341344","title":"Immunoglobulin expression and the humoral immune response is regulated by the non-canonical poly(A) polymerase TENT5C.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32341344","citation_count":58,"is_preprint":false},{"pmid":"28619709","id":"PMC_28619709","title":"Loss of FAM46C Promotes Cell Survival in Myeloma.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28619709","citation_count":58,"is_preprint":false},{"pmid":"28341836","id":"PMC_28341836","title":"FAM46C is critical for the anti-proliferation and pro-apoptotic effects of norcantharidin in hepatocellular carcinoma cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28341836","citation_count":41,"is_preprint":false},{"pmid":"32966780","id":"PMC_32966780","title":"The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32966780","citation_count":39,"is_preprint":false},{"pmid":"32963011","id":"PMC_32963011","title":"FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32963011","citation_count":38,"is_preprint":false},{"pmid":"31087039","id":"PMC_31087039","title":"Non-canonical RNA polyadenylation polymerase FAM46C is essential for fastening sperm head and flagellum in mice†.","date":"2019","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/31087039","citation_count":33,"is_preprint":false},{"pmid":"32141701","id":"PMC_32141701","title":"FAM46C controls antibody production by the polyadenylation of immunoglobulin mRNAs and inhibits cell migration in multiple myeloma.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32141701","citation_count":32,"is_preprint":false},{"pmid":"28123642","id":"PMC_28123642","title":"Antimetastatic effects of norcantharidin on hepatocellular carcinoma cells by up-regulating FAM46C expression.","date":"2017","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/28123642","citation_count":32,"is_preprint":false},{"pmid":"32807875","id":"PMC_32807875","title":"FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807875","citation_count":30,"is_preprint":false},{"pmid":"37035757","id":"PMC_37035757","title":"circRNA_17725 Promotes Macrophage Polarization towards M2 by Targeting FAM46C to Alleviate Arthritis.","date":"2023","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37035757","citation_count":27,"is_preprint":false},{"pmid":"32283544","id":"PMC_32283544","title":"FAM46C inhibits cell proliferation and cell cycle progression and promotes apoptosis through PTEN/AKT signaling pathway and is associated with chemosensitivity in prostate cancer.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32283544","citation_count":26,"is_preprint":false},{"pmid":"27770343","id":"PMC_27770343","title":"FAM46C Serves as a Predictor of Hepatic Recurrence in Patients with Resectable Gastric Cancer.","date":"2016","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27770343","citation_count":24,"is_preprint":false},{"pmid":"32176823","id":"PMC_32176823","title":"Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/32176823","citation_count":22,"is_preprint":false},{"pmid":"34048638","id":"PMC_34048638","title":"Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C.","date":"2021","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34048638","citation_count":17,"is_preprint":false},{"pmid":"32433990","id":"PMC_32433990","title":"Structural and Functional Analyses of the FAM46C/Plk4 Complex.","date":"2020","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/32433990","citation_count":16,"is_preprint":false},{"pmid":"30910647","id":"PMC_30910647","title":"FAM46C inhibits lipopolysaccharides-induced myocardial dysfunction via downregulating cellular adhesion molecules and inhibiting apoptosis.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30910647","citation_count":13,"is_preprint":false},{"pmid":"31585903","id":"PMC_31585903","title":"FAM46C suppresses gastric cancer by inhibition of Wnt/beta-catenin.","date":"2020","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/31585903","citation_count":11,"is_preprint":false},{"pmid":"32468032","id":"PMC_32468032","title":"NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/32468032","citation_count":10,"is_preprint":false},{"pmid":"30573978","id":"PMC_30573978","title":"The potential functions of FAM46C in oral squamous cell carcinoma.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30573978","citation_count":10,"is_preprint":false},{"pmid":"38484570","id":"PMC_38484570","title":"Mild hypothermia reduces lipopolysaccharide-induced microglial activation via down-regulation of Tent5c.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38484570","citation_count":9,"is_preprint":false},{"pmid":"38730656","id":"PMC_38730656","title":"Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38730656","citation_count":7,"is_preprint":false},{"pmid":"37358411","id":"PMC_37358411","title":"FAM46C Is an Interferon-Stimulated Gene That Inhibits Lentiviral Particle Production by Modulating Autophagy.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37358411","citation_count":6,"is_preprint":false},{"pmid":"38403115","id":"PMC_38403115","title":"The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis.","date":"2024","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/38403115","citation_count":5,"is_preprint":false},{"pmid":"37155154","id":"PMC_37155154","title":"FAM46C-mediated tumor heterogeneity predicts extramedullary metastasis and poorer survival in multiple myeloma.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37155154","citation_count":4,"is_preprint":false},{"pmid":"39532219","id":"PMC_39532219","title":"Induction of FAM46C expression mediated by DNMT3A downregulation is involved in early-onset preeclampsia through gene body methylation.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39532219","citation_count":4,"is_preprint":false},{"pmid":"39279976","id":"PMC_39279976","title":"The emerging role of FAM46C as a biomarker and therapeutic target in gastric adenocarcinoma.","date":"2024","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39279976","citation_count":3,"is_preprint":false},{"pmid":"37467675","id":"PMC_37467675","title":"Hsa-miR-1269a up-regulation fosters the malignant progression of esophageal squamous cell carcinoma via targeting FAM46C.","date":"2023","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/37467675","citation_count":3,"is_preprint":false},{"pmid":"40001499","id":"PMC_40001499","title":"Modulation of Autophagy by Oncosuppressor FAM46C and Its Implications for Cancer Therapy: An Intriguing Perspective.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40001499","citation_count":2,"is_preprint":false},{"pmid":"40427516","id":"PMC_40427516","title":"FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40427516","citation_count":1,"is_preprint":false},{"pmid":"42009655","id":"PMC_42009655","title":"TENT5C extends Odf1 poly(A) tail to sustain sperm morphogenesis and fertility.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42009655","citation_count":1,"is_preprint":false},{"pmid":"40421654","id":"PMC_40421654","title":"TENT5C functions as a corepressor in the ligand-bound glucocorticoid receptor and estrogen receptor α complexes.","date":"2025","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/40421654","citation_count":0,"is_preprint":false},{"pmid":"37654211","id":"PMC_37654211","title":"[Retracted] NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling.","date":"2023","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/37654211","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.20.644152","title":"TENT5C extends  <i>Odf1</i>  poly(A) tail to sustain sperm morphogenesis and fertility","date":"2025-03-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.20.644152","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.14.623596","title":"Efficient globin production during terminal erythropoiesis depends on the synergistic action of TENT5C poly(A) polymerase and LARP4/5","date":"2024-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.14.623596","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19224,"output_tokens":5510,"usd":0.070161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13954,"output_tokens":4430,"usd":0.09026,"stage2_stop_reason":"end_turn"},"total_usd":0.160421,"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\": 2017,\n      \"finding\": \"FAM46C/TENT5C encodes an active non-canonical poly(A) polymerase; catalytically-inactive mutant fails to enhance mRNA stability or induce cell death, establishing that enzymatic activity is required for its tumor-suppressive function in multiple myeloma.\",\n      \"method\": \"In vitro poly(A) polymerase assay, catalytic mutant re-introduction into MM cell lines, mRNA stability assays, Nanopore direct RNA-sequencing of poly(A) tails\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with catalytic mutant, replicated across multiple cell lines and in vivo KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"28931820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TENT5C polyadenylates immunoglobulin mRNAs in activated B cells, regulating their half-life and steady-state levels; catalytic activity knock-in mice display the same impaired antibody production phenotype as Tent5c-/- mice, confirming enzymatic activity is required.\",\n      \"method\": \"Nanopore direct RNA-sequencing for poly(A) tail length distribution, catalytic mutation knock-in mice, Tent5c-/- mouse model with immune response measurements, poly(A) tail-length assays on Ig mRNAs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — poly(A) tail profiling with direct RNA-seq, catalytic knock-in mice, KO mice with defined immune phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32341344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C selectively stabilizes mRNAs encoding ER-targeted proteins (ER protein import, folding, N-glycosylation, trafficking) and requires interaction with ER membrane resident proteins FNDC3A and FNDC3B for this activity; FAM46C activity is regulated by proteasomal degradation or inhibitory interaction with the ZZ domain of autophagic receptor p62, which sequesters it in p62+ aggregates and prevents its association with FNDC3 proteins.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation, mRNA stability assays, proteasome inhibition experiments, p62 ZZ-domain binding assay, MS-based proteomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple interaction partners validated, functional consequences of complex disruption measured, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32966780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C forms a complex with ER-associated protein FNDC3A; this complex requires FNDC3A for FAM46C to reside on the cytoplasmic side of the ER. The FAM46C/FNDC3A complex modulates secretion routes and impairs autophagy, leading to accumulation of intracellular protein aggregates and apoptosis in MM cells.\",\n      \"method\": \"Biochemical analysis/Co-IP, reconstitution of FAM46C in MM cells that lost it, FNDC3A depletion and expression rescue experiments, autophagy assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis via FNDC3A rescue experiment, multiple cell lines tested, replicated functional effects across independent labs (corroborates PMID 32966780)\",\n      \"pmids\": [\"32963011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of mammalian FAM46C at 2.35 Å reveals it is a prokaryotic-like poly(A) polymerase that preferentially uses ATP and extends A-rich RNA substrates; residues at positions 77, 290, and 298 are key determinants of enzymatic activity divergence from homolog FAM46B; MM-associated mutations at the catalytic site (D90G, D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, M270V) abolish or compromise PAP activity and anti-apoptotic suppression.\",\n      \"method\": \"X-ray crystallography (2.35 Å), site-directed mutagenesis, in vitro poly(A) polymerase biochemical assays, cell-based apoptosis assay with mutant variants\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus site-directed mutagenesis plus in vitro enzymatic assays in one study, multiple mutants systematically tested\",\n      \"pmids\": [\"34048638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C physically interacts with the serine/threonine kinase Plk4; crystal structure of FAM46C in complex with the Cryptic Polo-Box 1-2 (CPB1-2) domains of Plk4 was determined; this interaction recruits FAM46C to centrosomes; FAM46C inhibits Plk4 kinase activity and suppresses Plk4-induced centriole duplication independently of FAM46C's nucleotidyl transferase activity.\",\n      \"method\": \"Crystal structure of FAM46C-Plk4 CPB1-2 complex, structure-based mutational analyses, Co-IP, kinase activity assay, centriole duplication assay, xenograft model\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure with structure-based mutagenesis, kinase assay, functional centriole duplication assay in one study\",\n      \"pmids\": [\"32433990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C/TENT5C localizes to centrioles and inhibits Plk4 kinase activity, suppressing centriole overduplication and cancer cell invasion; this function is independent of its nucleotidyltransferase activity; FAM46C loss is detected in patient-derived colorectal cancer tissue correlating with advanced clinical stage.\",\n      \"method\": \"Co-IP (physical interaction with Plk4), immunofluorescence localization to centrioles, Plk4 kinase inhibition assay, centriole counting, invasion assay, xenograft model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase assay, live-cell imaging localization with functional consequence, xenograft validation, multiple orthogonal methods\",\n      \"pmids\": [\"32807875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM46C localizes specifically to the manchette (a transient microtubule-based structure) of spermatids in mouse testes; FAM46C knockout causes male sterility with headless spermatozoa; FAM46C does not exhibit protein kinase or AMPylation activity against general substrates in vitro.\",\n      \"method\": \"Immunofluorescence localization, gene knockout mouse model, intracytoplasmic sperm injection assay, RNA-seq of KO testes, in vitro kinase and AMPylation activity assays (negative for both)\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunolocalization, KO mouse with specific fertility phenotype, in vitro activity assays with negative controls\",\n      \"pmids\": [\"31087039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TENT5C poly(A) polymerase activity is required to extend poly(A) tails of Odf1 mRNA in late spermatids; absence of TENT5C catalytic activity causes shorter Odf1 poly(A) tails, failure of ODF1 protein accumulation at the spermatid neck, and production of headless spermatozoa with flagellar abnormalities, establishing Odf1 as a direct in vivo substrate critical for sperm morphogenesis.\",\n      \"method\": \"Catalytically-inactive TENT5C knock-in mice, transcriptome-wide poly(A) tail profiling, immunofluorescence for ODF1 localization, sperm morphology analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic knock-in mouse with poly(A) tail profiling and protein localization, identifying specific mRNA substrate with functional consequence, peer-reviewed\",\n      \"pmids\": [\"42009655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C polyadenylates immunoglobulin heavy and light chain mRNAs as direct substrates in plasma cells; FAM46C inactivation (CRISPR-Cas9) causes poly(A) tail shortening of Ig mRNAs, reducing their abundance and protein output; loss of FAM46C also upregulates MALAT1 lncRNA and activates PI3K/Rac1 signaling to increase myeloma cell migration.\",\n      \"method\": \"CRISPR-Cas9 FAM46C inactivation, poly(A) tail-length determination assays on Ig mRNAs, gene expression analysis, migration assay with PI3K/Rac1 pathway inhibitors\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct poly(A) tail measurement on specific substrates with CRISPR KO, functional migration assay, single lab\",\n      \"pmids\": [\"32141701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wild-type FAM46C overexpression in MM cells downregulates IRF4, CEBPB, and MYC while upregulating immunoglobulin light chain and HSPA5/BIP; CRISPR-mediated depletion of endogenous FAM46C activates ERK and antiapoptotic signaling and confers resistance to dexamethasone and lenalidomide; myeloma mutations in FAM46C abrogate its cytotoxicity.\",\n      \"method\": \"FAM46C overexpression with patient-derived mutants, CRISPR KO in MM cell lines, gene expression analysis, drug sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO and OE with defined molecular endpoints, multiple MM cell lines, single lab\",\n      \"pmids\": [\"28619709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of FAM46C in MM cells triggers activation of PI3K-Akt signaling, decreasing PTEN activity and increasing phosphorylation of Akt and its substrates both in vitro and in vivo; a selective PI3K inhibitor (PF-04691502) or Akt inhibitor (afuresertib) suppresses the augmented Akt phosphorylation in FAM46C-/- cells.\",\n      \"method\": \"CRISPR-generated FAM46C-/- MM cell clones, xenograft mouse model, western blotting for p-Akt and substrates, PTEN activity assay, PI3K/Akt inhibitor treatment, gene set enrichment analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with in vivo validation, biochemical Akt/PTEN measurements, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32176823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM46C is an interferon-stimulated gene; wild-type FAM46C expression in HEK-293T cells inhibits production of HIV-1-derived and HIV-1 lentiviruses through deregulation of autophagy (a pathway required for efficient lentiviral particle production), not through transcriptional or translational inhibition; frequent MM-associated mutant variants of FAM46C do not inhibit lentiviral production.\",\n      \"method\": \"Interferon stimulation assays, lentiviral production assays with WT vs. mutant FAM46C overexpression, autophagy perturbation experiments, translation inhibition controls\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional lentiviral production assay with WT vs. mutant FAM46C, autophagy mechanism dissected, single lab\",\n      \"pmids\": [\"37358411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TENT5C acts as a corepressor of both glucocorticoid receptor (GR) and estrogen receptor α (ERα); the third LXXLL motif of TENT5C directly interacts with ERα (supported by molecular dynamics simulations and Co-IP); mutation of the third LXXLL motif disrupts repression of ERα but not GR; TENT5C poly(A) polymerase activity is not required for repression of ERα.\",\n      \"method\": \"Co-immunoprecipitation (TENT5C with ERα), reporter assays (GR and ERα transcriptional activity), LXXLL motif mutagenesis, molecular dynamics simulations, catalytic mutant controls\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and reporter assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40421654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM46C is required for proper erythropoiesis; it stabilizes mRNA in a polymerase activity-dependent manner during red blood cell development; direct in vivo targets include transcripts encoding lysosome and mitochondria components, consistent with the need for organelle clearance during erythroid maturation; FAM46C upregulation in late erythroid stages is controlled by an erythroid-specific enhancer.\",\n      \"method\": \"FAM46C KO in erythroid cells, mRNA stability assays, erythroid differentiation assays, enhancer characterization, transcriptome analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with mRNA stability assays and defined cellular phenotype, enhancer experiment, single lab\",\n      \"pmids\": [\"38403115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TENT5C cooperates with LARP4/5 RNA-binding proteins to maintain globin mRNA poly(A) tails and hemoglobin production during terminal erythropoiesis; TENT5C catalytic mutant knock-in mice display microcytic hypochromic anemia; proteomics revealed a transient but specific association of TENT5C with LARP4/5; LARP4/5 depletion causes poly(A) tail shortening and downregulation of globin mRNAs; TENT5C is destabilized by CCR4-NOT-associated E3 ubiquitin ligase CNOT4.\",\n      \"method\": \"Catalytic mutant knock-in mice, poly(A) tail profiling, proteomic Co-IP (TENT5C-LARP4/5), LARP4/5 depletion, CNOT4-mediated ubiquitination/degradation assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic knock-in mice with phenotype, proteomic Co-IP, poly(A) profiling, multiple orthogonal methods; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C overexpression in HCC cells suppresses cell migration and invasion by suppressing TGF-β/Smad signaling and inhibiting epithelial-mesenchymal transition (EMT); antimetastatic effects of NCTD on HCC cells are partially rescued by FAM46C knockdown.\",\n      \"method\": \"FAM46C overexpression and knockdown in HCC cell lines, migration/invasion assays, western blotting for TGF-β/Smad pathway components and EMT markers\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway western blots with OE/KD, no direct mechanistic link established between FAM46C poly(A) activity and TGF-β/Smad\",\n      \"pmids\": [\"28123642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C promotes PTEN expression in prostate cancer cells by inhibiting PTEN ubiquitination, thereby suppressing AKT activation; FAM46C KD activates AKT and promotes cell proliferation.\",\n      \"method\": \"FAM46C knockdown and overexpression in prostate cancer cell lines, PTEN ubiquitination assay, AKT phosphorylation western blot, in vivo tumor growth assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ubiquitination assay without identification of specific E3 ligase or direct mechanistic connection to FAM46C PAP activity\",\n      \"pmids\": [\"32283544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TENT5C expression is regulated by DNMT3A-mediated gene body methylation; DNMT3A knockdown increases enrichment of DNMT3B and DNMT1 at the FAM46C gene body, elevating FAM46C transcription; elevated FAM46C suppresses trophoblast cell migration and invasion.\",\n      \"method\": \"Bisulfite sequencing of FAM46C gene body, DNMT3A siRNA knockdown, ChIP or methylation enrichment analysis, RNA-seq, migration/invasion rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect regulation mechanism, functional rescue experiments but no direct mechanistic link to FAM46C protein activity\",\n      \"pmids\": [\"39532219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TENT5C downregulation mediates the anti-inflammatory effects of mild hypothermia in LPS-stimulated microglia; TENT5C knockdown attenuates expression of pro-inflammatory genes (TNF-α, IL-1β, Agrn, Fpr2), NLRP3 and p-P65 levels, and ASC-speck formation; TENT5C overexpression potentiates these inflammatory indicators.\",\n      \"method\": \"siRNA knockdown of Tent5c in BV-2 microglial cells, LPS stimulation, RT-PCR, western blot for NLRP3 and p-P65, immunofluorescence for p-P65 and ASC-speck\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/OE with defined inflammatory phenotype but no direct molecular mechanism linking TENT5C poly(A) activity to NF-κB/NLRP3 pathway\",\n      \"pmids\": [\"38484570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TENT5C/FAM46C is a cytoplasmic non-canonical poly(A) polymerase that stabilizes specific mRNA subsets — including immunoglobulin mRNAs in plasma cells, ER-targeted protein mRNAs in secretory cells, globin mRNAs in erythroid cells, and Odf1 mRNA in spermatids — through its catalytic activity, with its enzymatic activity proven required for all major physiological functions; in addition to its RNA-regulatory role, TENT5C physically interacts with FNDC3A/B at the ER to modulate secretory trafficking and autophagy, with the autophagic receptor p62 sequestering TENT5C via its ZZ domain to limit its activity, and TENT5C also localizes to centrioles by binding the CPB1-2 domains of Plk4 to inhibit Plk4 kinase activity and suppress centriole duplication independently of its nucleotidyl transferase activity, while also acting as a corepressor of glucocorticoid and estrogen receptors via an LXXLL motif-dependent mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TENT5C (FAM46C) is a cytoplasmic non-canonical poly(A) polymerase that stabilizes defined mRNA subsets by extending their poly(A) tails, a function central to its role as a tumor suppressor in multiple myeloma and to terminal differentiation programs in secretory, erythroid, and germ cells [#0, #1]. Structurally it is a prokaryotic-like poly(A) polymerase that preferentially uses ATP to extend A-rich substrates, and myeloma-associated mutations at its catalytic or RNA-binding residues abolish polymerase activity and its pro-apoptotic suppression of malignant cells [#4]. Its catalytic activity is required across physiological contexts: it polyadenylates immunoglobulin heavy and light chain mRNAs in plasma cells to sustain antibody output [#1, #9], stabilizes ER-targeted protein mRNAs in secretory cells through interaction with the ER membrane proteins FNDC3A/FNDC3B, which tether it to the cytoplasmic face of the ER and couple it to secretory routing and autophagy [#2, #3], and extends the poly(A) tail of Odf1 mRNA in spermatids to drive sperm head morphogenesis [#8]. During terminal erythropoiesis it maintains globin mRNA poly(A) tails in cooperation with the LARP4/5 RNA-binding proteins and stabilizes transcripts encoding organelle-clearance machinery [#14, #15]. TENT5C activity is restrained by post-translational and sequestration mechanisms, including proteasomal degradation, CNOT4-mediated ubiquitination, and capture by the autophagy receptor p62 via its ZZ domain [#2, #15]. Independently of its enzymatic activity, TENT5C localizes to centrioles by binding the CPB1-2 domains of Plk4, inhibiting Plk4 kinase activity to suppress centriole overduplication and invasion [#5, #6], and acts as a corepressor of glucocorticoid and estrogen receptor \\u03b1 through an LXXLL-motif-dependent interaction [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that TENT5C is an enzyme rather than a passive scaffold, defining its non-canonical poly(A) polymerase activity as the basis of its tumor-suppressive cell-death function in myeloma.\",\n      \"evidence\": \"In vitro poly(A) polymerase assay with catalytically-inactive mutant re-introduction into MM lines, mRNA stability assays, and Nanopore direct RNA-seq of poly(A) tails\",\n      \"pmids\": [\"28931820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific endogenous mRNA substrates\", \"Mechanism coupling tail extension to cell death not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TENT5C function to downstream transcriptional programs and drug sensitivity, showing its loss activates survival signaling and confers resistance to myeloma therapeutics.\",\n      \"evidence\": \"FAM46C overexpression with patient-derived mutants and CRISPR KO in MM cell lines, gene expression analysis, drug sensitivity assays\",\n      \"pmids\": [\"28619709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRF4/MYC/CEBPB changes not tied directly to poly(A) activity\", \"ERK activation mechanism downstream of loss unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a germ-cell role by localizing TENT5C to the spermatid manchette and showing knockout causes headless-sperm sterility, while ruling out kinase and AMPylation activities.\",\n      \"evidence\": \"Immunofluorescence, KO mouse model, ICSI assay, and negative in vitro kinase/AMPylation assays\",\n      \"pmids\": [\"31087039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular substrate driving the phenotype\", \"Did not establish whether poly(A) activity underlies sterility\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated immunoglobulin mRNAs are direct physiological substrates, with catalytic knock-in mice phenocopying knockouts to prove enzymatic activity drives antibody production.\",\n      \"evidence\": \"Nanopore direct RNA-seq poly(A) profiling, catalytic knock-in and Tent5c-/- mice with immune phenotyping; corroborated by CRISPR-KO poly(A) tail measurement on Ig mRNAs in plasma cells\",\n      \"pmids\": [\"32341344\", \"32141701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate selection mechanism for Ig mRNAs not defined\", \"MALAT1/PI3K-Rac1 migration link is indirect\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a spatial and regulatory framework for TENT5C's RNA activity, placing it on the cytoplasmic face of the ER via FNDC3A/B to stabilize secretory mRNAs and modulate trafficking and autophagy, with p62 ZZ-domain sequestration and proteasomal turnover as restraints.\",\n      \"evidence\": \"Reciprocal Co-IP, biochemical fractionation, FNDC3A depletion/rescue, p62 ZZ-domain binding assay, mRNA stability and autophagy assays across two independent labs\",\n      \"pmids\": [\"32966780\", \"32963011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FNDC3 tethering selects ER-targeted mRNA substrates is unclear\", \"Quantitative balance between RNA stabilization and aggregate-induced apoptosis not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an enzymatic-activity-independent function at the centriole, showing TENT5C binds the Plk4 CPB1-2 domains to inhibit Plk4 kinase and suppress centriole overduplication and invasion.\",\n      \"evidence\": \"Co-crystal structure of FAM46C-Plk4 CPB1-2, structure-based mutagenesis, Co-IP, kinase and centriole-duplication assays, xenograft; corroborated by IF localization and invasion assays\",\n      \"pmids\": [\"32433990\", \"32807875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the centriolar pool is partitioned from the cytoplasmic RNA-regulatory pool is unknown\", \"In vivo contribution of Plk4 inhibition to tumor suppression not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected TENT5C loss to a defined survival pathway in myeloma by showing it stabilizes PTEN function and its absence drives PI3K-Akt activation reversible by pathway inhibitors.\",\n      \"evidence\": \"CRISPR FAM46C-/- clones, xenograft, p-Akt/PTEN biochemistry, PI3K/Akt inhibitor treatment, GSEA\",\n      \"pmids\": [\"32176823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between poly(A) activity and PTEN/PI3K not established\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural basis for catalysis, defining TENT5C as a prokaryotic-like ATP-preferring poly(A) polymerase and mapping how disease mutations disable activity.\",\n      \"evidence\": \"2.35 \\u00c5 X-ray crystal structure, site-directed mutagenesis, in vitro PAP assays, cell-based apoptosis assays with mutants\",\n      \"pmids\": [\"34048638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of an RNA-bound or partner-bound complex not solved\", \"Determinants of in vivo substrate specificity not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the substrate-stabilization paradigm to erythropoiesis, showing TENT5C maintains globin mRNA poly(A) tails with LARP4/5 cofactors and stabilizes organelle-clearance transcripts under enhancer control.\",\n      \"evidence\": \"Erythroid KO, mRNA stability and differentiation assays, enhancer characterization, transcriptomics; preprint catalytic knock-in mice with anemia, LARP4/5 proteomic Co-IP, and CNOT4 degradation assay\",\n      \"pmids\": [\"38403115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LARP4/5 cooperation evidence is from a preprint not yet peer-reviewed\", \"How CNOT4 turnover is timed during differentiation is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-RNA nuclear-receptor function, identifying TENT5C as an LXXLL-motif corepressor of GR and ER\\u03b1 independent of its polymerase activity.\",\n      \"evidence\": \"Co-IP with ER\\u03b1, GR/ER\\u03b1 reporter assays, LXXLL mutagenesis, molecular dynamics, catalytic mutant controls\",\n      \"pmids\": [\"40421654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous target genes of TENT5C-mediated repression not defined\", \"Single-lab, partly simulation-supported interaction\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Closed the germ-cell mechanism by identifying Odf1 mRNA as the direct in vivo substrate whose tail extension by TENT5C is required for sperm head assembly.\",\n      \"evidence\": \"Catalytic knock-in mice, transcriptome-wide poly(A) profiling, ODF1 immunofluorescence, sperm morphology analysis\",\n      \"pmids\": [\"42009655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional spermatid substrates contribute to the phenotype not excluded\", \"Recruitment of TENT5C to specific spermatid mRNAs not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TENT5C selects its tissue-specific mRNA substrates and how its three biochemical modes \\u2014 cytoplasmic poly(A) polymerase, centriolar Plk4 inhibitor, and nuclear-receptor corepressor \\u2014 are spatially and temporally partitioned within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate recognition across cell types\", \"No structural or single-cell data resolving the multiple functional pools\", \"Relationship between RNA-dependent and RNA-independent functions in tumor suppression unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 4, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 8, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FNDC3A\", \"FNDC3B\", \"PLK4\", \"SQSTM1\", \"LARP4\", \"LARP5\", \"CNOT4\", \"ESR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}