Affinage

TENT5A

Terminal nucleotidyltransferase 5A · UniProt Q96IP4

Length
442 aa
Mass
49.7 kDa
Annotated
2026-06-10
18 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TENT5A is a non-canonical cytoplasmic poly(A) polymerase that selectively extends the poly(A) tails of a defined set of mRNAs—particularly those encoding secreted and ER-targeted proteins—thereby stabilizing the transcripts and increasing their protein output (PMID:33882302, PMID:40240603). Its catalytic poly(A) polymerase activity is intrinsic and requires conserved active-site residues, and the enzyme shuttles between the nucleus, where it is proximal to active chromatin, and the cytosol, where it associates with the endoplasmic reticulum (PMID:32528962). ER tethering, mediated by Fndc3 proteins, is required for its cytosolic polyadenylation activity, and target re-adenylation depends on spatial co-localization of the mRNA with ER-resident TENT5A (PMID:40240603, PMID:42161934). Through this mechanism TENT5A promotes osteoblast collagen production by polyadenylating Col1α1/Col1α2 transcripts, and its loss causes bone fragility and skeletal hypomineralization in mice; a homozygous p.Ile324Met variant in a human patient produces shortened COL1A1/COL1A2 poly(A) tails, reduced collagen, and impaired matrix mineralization (PMID:33882302, PMID:41908159). The same activity stabilizes insulin mRNA to sustain beta-cell insulin content (PMID:42161934), extends vaccine mRNA poly(A) tails in macrophages to support antibody responses (PMID:40240603), and binds and stabilizes MYC mRNA to reinforce stemness and chemoresistance in osteosarcoma (PMID:41616089). TENT5A expression is driven by EGR1, and in hepatocellular carcinoma it interacts with RPL35 and negatively regulates mTOR signaling (PMID:39570560); it also physically interacts with Smad1/Smad4 to promote BMP signaling during Xenopus pre-placodal ectoderm formation (PMID:30291163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2018 Medium

    Before its enzymatic role was defined, FAM46A was placed in a developmental signaling context, establishing a physical link to BMP/Smad signaling.

    Evidence Co-IP showing Fam46a–Smad1/Smad4 interaction and morpholino knockdown in Xenopus embryos

    PMID:30291163

    Open questions at the time
    • Does not connect the Smad interaction to poly(A) polymerase activity
    • Mechanism by which Fam46a potentiates BMP signaling unresolved
    • Single organism (Xenopus), no mammalian validation
  2. 2020 Medium

    Established that FAM46A/TENT5A is a bona fide non-canonical poly(A) polymerase whose catalytic activity is functionally required, and characterized its dual nucleocytoplasmic localization and proteasomal turnover.

    Evidence Active-site site-directed mutagenesis, subcellular fractionation/immunofluorescence, and hemin-induced hemoglobinization in K562 cells

    PMID:32528962

    Open questions at the time
    • Direct mRNA substrates not identified
    • Functional significance of nuclear pool versus cytosolic/ER pool unclear
    • Single cell line
  3. 2021 High

    Identified the first physiological substrate class and tissue role: TENT5A polyadenylates collagen and secreted-protein mRNAs to drive osteoblast function, linking enzymatic activity to a skeletal phenotype.

    Evidence Direct RNA sequencing of polyadenylation targets and Tent5a knockout mouse with skeletal phenotyping

    PMID:33882302

    Open questions at the time
    • Does not define the substrate-selection determinant
    • ER-tethering requirement not yet established
    • Mechanism of transcript selectivity unresolved
  4. 2022 Medium

    Extended the regulatory reach of TENT5A to muscle by linking its loss to reduced myogenin and impaired fiber maturation.

    Evidence siRNA knockdown in C2C12 cells with proliferation/migration assays and in vivo muscle fiber analysis

    PMID:35137485

    Open questions at the time
    • No direct polyadenylation assay demonstrating myogenin mRNA is a substrate
    • Direct versus indirect effect on myogenin not distinguished
    • Single lab
  5. 2024 Medium

    Connected TENT5A to upstream transcriptional control (EGR1) and a downstream ribosome/mTOR axis, defining a tumor-suppressive role in hepatocellular carcinoma.

    Evidence ChIP and luciferase (EGR1–promoter), Co-IP/GST pull-down with MS (TENT5A–RPL35), and Gly122 mutagenesis with gain/loss-of-function assays

    PMID:39570560

    Open questions at the time
    • How the RPL35 interaction mechanistically suppresses mTOR is unclear
    • Relationship between RPL35 binding and poly(A) polymerase activity unresolved
    • Single lab
  6. 2025 High

    Defined the spatial logic of substrate selection: TENT5A re-adenylates ER-targeted mRNAs based on their ER co-localization, with direct functional consequence for mRNA-vaccine antibody responses.

    Evidence Nanopore direct poly(A) tail sequencing in macrophages, ER-targeting reporter constructs, and TENT5A KO mice immunized with mRNA vaccines

    PMID:40240603

    Open questions at the time
    • The molecular tether linking TENT5A to the ER not yet identified in this study
    • Determinants of which ER-associated mRNAs are selected incomplete
  7. 2026 High

    Identified the ER-tethering mechanism (Fndc3 proteins) as a prerequisite for cytosolic activity and extended the substrate repertoire to insulin mRNA in beta cells.

    Evidence RNAi screen, Tent5a KO and overexpression in INS-1E cells and human islet microtissues with mRNA half-life and poly(A) tail measurements; Fndc3 interaction for localization

    PMID:42161934

    Open questions at the time
    • Stoichiometry and regulation of the TENT5A–Fndc3 interaction not detailed
    • How ER tethering enables catalysis mechanistically unresolved
  8. 2026 Medium

    Demonstrated direct mRNA binding and poly(A) extension on MYC, mapping the activity to the PAP/OAS1 domain and establishing a druggable pro-tumorigenic role in osteosarcoma.

    Evidence Biochemical TENT5A–MYC mRNA binding and poly(A) tail analysis, xenografts, patient-derived organoids, and pharmacologic inhibition

    PMID:41616089

    Open questions at the time
    • Apparent contrast with tumor-suppressive role in HCC not reconciled
    • Substrate-binding specificity determinants incomplete
    • Single lab
  9. 2026 Medium

    Confirmed in human disease that TENT5A polyadenylation selectively stabilizes ECM mRNAs, with a patient variant causally linked to collagen and mineralization defects.

    Evidence Nanopore direct poly(A) tail sequencing in patient fibroblasts carrying p.Ile324Met with matrix mineralization and osteogenic assays

    PMID:41908159

    Open questions at the time
    • Single patient
    • How the I324M residue impairs catalysis or substrate selection not structurally defined
    • Basis of ECM/regulatory-gene selectivity unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TENT5A recognizes its selective substrate set and how its opposing roles across tissues (tumor-suppressive in HCC versus MYC-stabilizing in osteosarcoma) are reconciled remain unresolved.
  • No structural model of substrate recognition
  • Determinants of ER-associated transcript selectivity unknown
  • Context-dependent pro- versus anti-tumor function unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 2 GO:0016740 transferase activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2
Partners
FNDC3RPL35SMAD1SMAD4

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 TENT5A is a cytoplasmic poly(A) polymerase that is induced during osteoblast differentiation and directly polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression and promoting bone mineralization. Tent5a knockout mice display bone fragility and skeletal hypomineralization resulting from quantitative and qualitative collagen defects. Direct RNA sequencing to identify polyadenylation targets; Tent5a knockout mouse model with skeletal phenotype analysis; osteoblast differentiation assays Cell reports High 33882302
2020 FAM46A (TENT5A) is a non-canonical poly(A) polymerase that localizes as a nucleocytoplasmic shuttle protein; in the cytosol it is closely associated with the ER and is modified by Tyr-phosphorylation, while in the nucleus it is proximal to active transcription chromatin regions. Its poly(A) polymerase activity (confirmed by site-directed mutagenesis) is essential for promoting hemin-induced hemoglobinization in K562 cells. It is a cell cycle-dependent poly-ubiquitinated protein degraded by the proteasome. Site-directed mutagenesis of active-site residues; subcellular fractionation; immunofluorescence localization; proteasome inhibitor treatment; K562 overexpression/hemin induction assays Frontiers in cell and developmental biology Medium 32528962
2018 In Xenopus, Fam46a physically interacts with Smad1/Smad4 and positively regulates BMP signaling, which is required for pre-placodal ectoderm (PPE) formation. Fam46a knockdown causes abnormalities in eye formation and body color, and reduces PPE gene expression while expanding neural crest formation. Co-immunoprecipitation (Fam46a–Smad1/Smad4 interaction); morpholino knockdown in Xenopus embryos with in situ hybridization and phenotypic readouts Development (Cambridge, England) Medium 30291163
2022 TENT5A regulates muscle fiber maturation by maintaining the stability/expression of myogenin mRNA. Tent5a knockdown in C2C12 myoblasts inhibits cell proliferation and migration, inhibits type I muscle fiber maturation in vitro and in vivo, and is associated with decreased myogenin expression. siRNA knockdown in C2C12 cells; CCK-8 proliferation assay; wound-healing migration assay; immunofluorescence; qPCR for myogenin; in vivo muscle fiber analysis Cell proliferation Medium 35137485
2025 TENT5A poly(A) polymerase is induced by mRNA vaccines (e.g., mRNA-1273) in macrophages and extends the poly(A) tails of vaccine mRNAs encoding ER-targeted proteins (e.g., spike antigen) from ~100 to up to ~200 nucleotides, stabilizing target mRNAs. Re-adenylation efficiency depends on spatial co-localization of the mRNA with ER-resident TENT5A. TENT5A deficiency in mice reduces specific immunoglobulin production after mRNA vaccination. Nanopore direct RNA sequencing of poly(A) tails in macrophages and cell lines; TENT5A KO mice immunized with mRNA vaccines; knockdown/KO in macrophages; synthetic mRNA reporter constructs targeting or not targeting ER Nature High 40240603
2024 TENT5A is transcriptionally activated by EGR1, which directly binds the TENT5A promoter. TENT5A in turn interacts with RPL35 (identified by Co-IP, GST pull-down, and mass spectrometry), participates in ribosome biogenesis, and exerts a negative regulatory effect on the mTOR pathway, suppressing HCC cell proliferation and metastasis. Residue Gly122 is critical for TENT5A function in HCC. Chromatin immunoprecipitation and dual-luciferase reporter assay (EGR1–TENT5A promoter); Co-IP and GST pull-down with MS (TENT5A–RPL35 interaction); gain- and loss-of-function assays; site-directed mutagenesis (Gly122) Cellular oncology (Dordrecht, Netherlands) Medium 39570560
2026 TENT5A directly binds MYC mRNA via its PAP/OAS1 domain, extends its poly(A) tail, and stabilizes the MYC transcript, thereby reinforcing MYC-driven stemness and chemoresistance in osteosarcoma. Pharmacologic inhibition of TENT5A shortens MYC mRNA poly(A) tails and reverses chemoresistance. Biochemical binding assays (TENT5A–MYC mRNA); poly(A) tail length analysis; gain- and loss-of-function assays; orthotopic xenografts; patient-derived organoids; pharmacologic inhibition Cancer research Medium 41616089
2026 TENT5A is a positive regulator of insulin production in pancreatic beta cells. Its cytosolic poly(A) polymerase activity extends the poly(A) tails of insulin mRNA, enhancing mRNA stability and increasing insulin content. TENT5A is tethered to the ER via Fndc3 proteins, and this ER localization is required for its cytosolic polyadenylation activity. Tent5a KO cells show shortened insulin mRNA half-life and reduced insulin content. RNAi functional screen; Tent5a KO cells (INS-1E); overexpression in INS-1E and human islet microtissues; poly(A) tail length measurement; mRNA half-life assay; subcellular localization via Fndc3 interaction Nature communications High 42161934
2026 A homozygous TENT5A variant (p.Ile324Met) in a human patient leads to shortened poly(A) tails on COL1A1 and COL1A2 transcripts in patient-derived fibroblasts, with reduced collagen expression and impaired matrix mineralization, confirming that TENT5A polyadenylation activity stabilizes ECM mRNAs in osteoblast-lineage cells. The poly(A) tail shortening is selective for ECM and regulatory genes, sparing housekeeping genes. Nanopore direct RNA sequencing of poly(A) tails in patient fibroblasts; qPCR and RNA-seq; matrix mineralization assay; osteogenic induction JBMR plus Medium 41908159

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. Journal of medical genetics 57 29358272
2021 Cytoplasmic polyadenylation by TENT5A is required for proper bone formation. Cell reports 41 33882302
2016 Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia. Mammalian genome : official journal of the International Mammalian Genome Society 32 26803617
2007 Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs. Annals of human genetics 32 17803723
2015 Association of the FAM46A gene VNTRs and BAG6 rs3117582 SNP with non small cell lung cancer (NSCLC) in Croatian and Norwegian populations. PloS one 24 25884493
2025 Re-adenylation by TENT5A enhances efficacy of SARS-CoV-2 mRNA vaccines. Nature 23 40240603
2014 Susceptibility to large-joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 21 25231575
2018 Fam46a regulates BMP-dependent pre-placodal ectoderm differentiation in Xenopus. Development (Cambridge, England) 20 30291163
2022 Tent5a modulates muscle fiber formation in adolescent idiopathic scoliosis via maintenance of myogenin expression. Cell proliferation 18 35137485
2014 Association of variable number of tandem repeats in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with susceptibility to tuberculosis. PloS one 15 24625963
2009 Family-with-sequence-similarity-46, member A (Fam46a) gene is expressed in developing tooth buds. Archives of oral biology 14 19740458
2020 Overexpression of FAM46A, a Non-canonical Poly(A) Polymerase, Promotes Hemin-Induced Hemoglobinization in K562 Cells. Frontiers in cell and developmental biology 8 32528962
2024 TENT5A mediates the cancer-inhibiting effects of EGR1 by suppressing the protein stability of RPL35 in hepatocellular carcinoma. Cellular oncology (Dordrecht, Netherlands) 4 39570560
2025 TENT5A Increases Glioma Malignancy and Promotes its Progression. Recent patents on anti-cancer drug discovery 3 38204269
2023 A Genetic Variant of FAM46A is Associated With the Development of Adolescent Idiopathic Scoliosis in the Chinese Population. Spine 2 37141460
2026 TENT5A Maintains MYC mRNA Stability to Enhance Osteosarcoma Stemness. Cancer research 0 41616089
2026 Impaired bone matrix turnover with selective small bone fragility in a child with TENT5A-associated osteogenesis imperfecta. JBMR plus 0 41908159
2026 Polyadenylation of insulin mRNA by Tent5a regulates pancreatic beta cells. Nature communications 0 42161934

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