Affinage

TENT4B

Terminal nucleotidyltransferase 4B · UniProt Q8NDF8

Length
572 aa
Mass
63.3 kDa
Annotated
2026-06-10
15 papers in source corpus 13 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TENT4B (PAPD5) is a non-canonical poly(A) polymerase that controls RNA stability in opposite directions depending on substrate, acting as a single-polypeptide enzyme that binds RNA through its C-terminal basic region and polymerizes nucleotides without an accessory RNA-binding cofactor (PMID:21788334). On mRNA, TENT4B (together with TENT4A) builds mixed poly(A) tails in which intermittent non-adenosine residues — most commonly guanosine — are interspersed; a single guanosine is sufficient to stall the CCR4-NOT deadenylase, so this guanylation shields transcripts from rapid deadenylation and sustains mRNA half-life and abundance (PMID:30026317). The same adenylating activity instead marks several non-coding RNAs for turnover: TENT4B adds oligo(A) tails to H/ACA box snoRNA/scaRNA processing intermediates that are then trimmed by PARN (PMID:22442037), adenylates mature miR-21 and other miRNAs to drive their PARN-dependent degradation (PMID:25049417), and oligoadenylates the telomerase RNA TERC to route it for EXOSC10-mediated decay, such that silencing TENT4B in DKC1-mutant cells restores TERC, telomerase activity, and telomere length (PMID:30728146, PMID:32559291, PMID:32320679). TENT4B is a determinant of HBV persistence: it physically associates with viral RNA and protects poly(A) tail integrity through the PRE stem-loop alpha element, and it is the cellular target of the HBV inhibitor RG7834, which engages its catalytic domain (PMID:30365161, PMID:33046485, PMID:34191584). Dysregulated TENT4B is also pathogenic in Huntington's disease models, where YY1 sequestration derepresses PAPD5, increasing miRNA adenylation and activating a TAB2-TAK1-MKK4-JNK pro-apoptotic cascade that a small-molecule PAPD5 inhibitor mitigates (PMID:40204699).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2011 High

    Established that PAPD5 is an autonomous RNA-adenylating enzyme, answering whether mammalian non-canonical poly(A) polymerases require a separate RNA-binding subunit as their yeast counterparts do.

    Evidence In vitro polyadenylation assays with recombinant PAPD5 plus C-terminal deletion analysis

    PMID:21788334

    Open questions at the time
    • Did not identify physiological RNA substrates in cells
    • Catalytic versatility beyond adenylation not addressed
  2. 2012 High

    Defined a tailing-and-trimming logic for non-coding RNA maturation by showing PAPD5 oligoadenylates H/ACA snoRNA processing intermediates that PARN then trims.

    Evidence Reciprocal siRNA knockdown of PAPD5 and PARN with Northern blotting and 3'-end sequencing in human cells

    PMID:22442037

    Open questions at the time
    • Substrate selectivity determinants unknown
    • Whether tailing promotes maturation versus degradation context-dependent
  3. 2014 Medium

    Extended PAPD5 adenylation to mature miRNAs, showing it adenylates miR-21 to trigger PARN-dependent 3'-to-5' decay and thereby relieve repression of target mRNAs.

    Evidence siRNA knockdown plus small-RNA sequencing of adenylated isomiRs and target mRNA microarray profiling

    PMID:25049417

    Open questions at the time
    • Breadth of miRNA substrate repertoire not defined
    • Direct enzyme-substrate contact not shown in this system
  4. 2016 Medium

    Placed PAPD5 within a regulatory circuit by showing the intronic miR-4728-3p inhibits PAPD5 to stabilize miR-21, reinforcing the adenylation-then-degradation model.

    Evidence miRNA transfection/inhibition with PAPD5 activity and miR-21 abundance measurements

    PMID:27752128

    Open questions at the time
    • Mechanism of PAPD5 inhibition by miR-4728-3p indirect
    • Single lab, builds on prior mechanism
  5. 2018 High

    Resolved how TENT4 enzymes stabilize rather than destabilize mRNA by demonstrating they synthesize mixed tails whose guanosine residues block CCR4-NOT deadenylation.

    Evidence Recombinant protein tail-synthesis assays, single-G insertion deadenylation assays, and knockdown half-life measurements

    PMID:30026317

    Open questions at the time
    • What dictates guanosine versus adenosine incorporation in vivo unknown
    • Structural basis of CCR4-NOT impediment not resolved
  6. 2019 High

    Connected PAPD5 to telomere biology by showing it oligoadenylates TERC for EXOSC10 degradation, making its inhibition a strategy to rescue telomerase in DKC1-mutant cells.

    Evidence RNAi silencing in DKC1-mutant hESCs with TERC level, telomerase activity, and telomere length readouts, replicated across groups

    PMID:30728146 PMID:32320679 PMID:32559291

    Open questions at the time
    • Recruitment of PAPD5 to TERC not mechanistically defined
    • Selectivity for TERC over other ncRNAs unexplained
  7. 2019 High

    Identified PAPD5/7 as the host targets of the HBV inhibitor RG7834 and as required for HBV RNA stability, establishing them as antiviral drug targets.

    Evidence Yeast three-hybrid target screen, catalytic-domain drug mapping, and siRNA knockdown phenocopy of HBV mRNA destabilization, replicated across labs

    PMID:30365161 PMID:33046485 PMID:34191584

    Open questions at the time
    • Functional redundancy between PAPD5 and PAPD7 only partially partitioned
    • How viral RNA recruits the enzymes not yet defined here
  8. 2020 Medium

    Showed PAPD5/7 physically associate with HBV RNA and that blocking their activity shortens the viral poly(A) tail and accelerates decay, providing the mechanistic basis for RG7834 action.

    Evidence RNA co-immunoprecipitation, RG7834-sensitive polyadenylation assays, poly(A) tail analysis, and double-knockout cells

    PMID:33046485

    Open questions at the time
    • Single lab
    • Direct versus indirect RNA association not distinguished
  9. 2021 Medium

    Partitioned the roles of the two enzymes and mapped the cis-element, showing PAPD5 dominantly protects HBV poly(A) integrity via the PRE stem-loop alpha while PAPD7 is a backup.

    Evidence Individual/double CRISPR knockouts, poly(A) tail sequencing, and PRE stem-loop alpha mutagenesis

    PMID:34191584

    Open questions at the time
    • Molecular contact between PAPD5 and stem-loop alpha not structurally resolved
    • Single lab
  10. 2025 Medium

    Implicated PAPD5 in neurodegeneration by showing YY1-driven derepression elevates PAPD5, increasing miRNA adenylation and activating a JNK pro-apoptotic pathway that an inhibitor reverses.

    Evidence HD cell and iPSC-neuron models with miRNA adenylation profiling, pathway epistasis, and BCH001 inhibitor rescue

    PMID:40204699

    Open questions at the time
    • Causal chain from individual miRNAs to JNK activation not fully dissected
    • Single lab
  11. 2026 Medium

    Tested whether TENT4B has intrinsic synthetic capacity beyond templated tailing, showing it performs primer- and template-independent de novo RNA polymerization from free NTPs and NDPs.

    Evidence In vitro assays with recombinant TENT4B, pyrophosphate detection, labeled NTP incorporation, and primer-free product sequencing (preprint)

    PMID:41847027

    Open questions at the time
    • Preprint, not peer-reviewed and single lab
    • Physiological relevance of de novo synthesis in cells unknown
    • Self-limited guanosine polymerization mechanism unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TENT4B selects between guanosine incorporation that stabilizes mRNA and oligoadenylation that targets ncRNAs for decay, and how it is recruited to specific substrates, remains unresolved.
  • No structural model of substrate selection or nucleotide choice
  • Recruitment mechanisms to TERC, snoRNAs, miRNAs, and HBV RNA undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0016740 transferase activity 3 GO:0003723 RNA binding 2
Localization
GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4
Partners
EXOSC10PARNTENT4A

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 TENT4B (PAPD5) and TENT4A (PAPD7) are the enzymes responsible for mRNA guanylation; purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues (most commonly guanosine). A single guanosine residue in the tail is sufficient to impede the CCR4-NOT deadenylase complex, shielding mRNA from rapid deadenylation. Depletion of both TENT4A and TENT4B decreases mRNA half-life and abundance in cells. Biochemical purification of recombinant proteins, in vitro tail-synthesis assay, deadenylation assay with CCR4-NOT, siRNA knockdown with mRNA half-life measurement Science High 30026317
2011 Recombinant PAPD5 catalyzes polyadenylation of diverse RNA substrates in vitro as a single polypeptide without a protein cofactor, in contrast to its yeast homolog Trf4p which requires a separate RNA-binding subunit. The C-terminal basic amino acid stretch of PAPD5 is involved in binding the RNA substrate. In vitro polyadenylation assay with recombinant PAPD5 expressed in mammalian cells and bacteria; deletion/domain analysis of C-terminal basic region RNA High 21788334
2012 PAPD5 is responsible for adding oligo(A) tails to processing intermediates of H/ACA box snoRNAs (and scaRNAs) in human cells; these oligoadenylated intermediates are subsequently trimmed by PARN. Knockdown of PAPD5 abolishes accumulation of oligoadenylated snoRNA stubs. PARN is concentrated in nucleoli and Cajal bodies consistent with this role. siRNA knockdown of PAPD5 and PARN in human cells; Northern blotting and sequencing of snoRNA 3'-end intermediates; subcellular fractionation/immunofluorescence of PARN RNA High 22442037
2014 PAPD5 adenylates the 3' end of mature miR-21 in human cells; PAPD5 knockdown causes increased miR-21 levels, while PARN degrades adenylated miR-21 in the 3'-to-5' direction. This tailing-and-trimming pathway results in down-regulation of miR-21 target mRNAs. siRNA knockdown of PAPD5 and exoribonucleases; small-RNA sequencing to detect adenylated miR-21 isomiRs; microarray profiling of target mRNA expression changes Proceedings of the National Academy of Sciences Medium 25049417
2019 PAPD5 (and PAPD7) oligoadenylates the telomerase RNA component TERC, destabilizing it. Knockdown or inhibition of PAPD5 in DKC1-mutant cells partially restores TERC levels and telomerase activity. The PAPD5–EXOSC10 axis mediates TERC degradation downstream of oligoadenylation. RNAi knockdown of PAPD5 in hESCs with DKC1_A353V mutation; measurement of TERC levels, telomerase activity, and telomere length; genetic silencing of PAPD5 as rescue experiment Blood High 30728146 32320679 32559291
2019 PAPD5 and PAPD7 are identified as the cellular protein targets of the HBV inhibitor RG7834 via yeast three-hybrid screen; the drug interaction was mapped to the catalytic domains of both enzymes. PAPD5 and PAPD7 are required for HBV RNA stabilization: knockdown phenocopies RG7834 treatment by destabilizing HBV mRNA without affecting transcription, and simultaneous knockdown of both shows the greatest effect, indicating functional redundancy. Compound-based yeast three-hybrid screen; domain-mapping of RG7834 binding to catalytic domain; siRNA knockdown of PAPD5/7 in HBV-infected hepatocytes; HBV mRNA stability assay Hepatology High 30365161 33046485 34191584
2020 In HBV-expressing cells, PAPD5 and PAPD7 are physically associated with viral RNA. Inhibition of their polyadenylating activities by RG7834 leads to poly(A) tail shortening of HBV mRNA followed by accelerated nuclear and cytoplasmic degradation. In PAPD5/7 double-knockout cells, viral transcripts with normal poly(A) length can initially be synthesized but become shortened within hours. RNA co-immunoprecipitation (PAPD5/7 with HBV RNA); biochemical polyadenylation assay susceptibility to RG7834; poly(A) tail length analysis; PAPD5/7 double-knockout cell lines Antimicrobial Agents and Chemotherapy Medium 33046485
2021 PAPD5 plays a dominant role in stabilizing HBV RNA by protecting the integrity of its poly(A) tail (PAPD5 KO impairs poly(A) tail integrity); PAPD7 serves as a second line of protection without measurable poly(A) tail effects alone. The stem-loop alpha sequence within the viral PRE is essential for maintaining poly(A) tail integrity and for sensitivity to PAPD5/7 inhibitors. Both PAPD5 and PAPD7 double-KO is required to reduce HBsAg production. Individual and double CRISPR knockout of PAPD5/7; poly(A) tail length sequencing; site-directed mutagenesis of viral PRE stem-loop alpha; inhibitor resistance assays Journal of Virology Medium 34191584
2016 miR-4728-3p (encoded in the HER2 intron) stabilizes miR-21-5p by inhibiting PAPD5, establishing that PAPD5-mediated 3' adenylation of miR-21-5p promotes its degradation in a PARN-dependent manner. miRNA transfection and inhibition experiments; PAPD5 expression and activity measurement after miR-4728-3p manipulation; miR-21-5p abundance assay Scientific Reports Medium 27752128
2025 In Huntington's disease models, the transcriptional repressor YY1 is sequestered to RNA foci and protein aggregates, leading to derepression and upregulation of PAPD5. Elevated PAPD5 increases adenylation of a subset of miRNAs (including miR-7-5p), reducing their levels, which activates the TAB2-TAK1-MKK4-JNK pro-apoptotic pathway and causes neuronal death. A small-molecule PAPD5 inhibitor (BCH001) mitigates this cell death. HD cell and iPSC-derived neuron models; PAPD5 expression and miRNA adenylation profiling; YY1 localization studies; TAK1-MKK4-JNK pathway activation assays; BCH001 inhibitor rescue experiments in disease models Nature Communications Medium 40204699
2026 Recombinant TENT4B can perform primer- and template-independent de novo RNA polymerization from free NTPs, consuming ATP to yield inorganic pyrophosphate and oligomeric poly-adenosine RNA products. The de novo synthesis efficiency is similar whether or not a primer is included. Guanosine nucleotide polymerization is self-limited and yields a 3'-exonuclease-resistant oligonucleotide. Nucleotide diphosphates can also serve as substrates. In vitro biochemical assay with recombinant TENT4B; ATP consumption / pyrophosphate detection; 5'-radiolabeled γ-phosphate-modified NTP incorporation; primer-free RNA product sequencing; comparison across NTP types and concentrations bioRxivpreprint Medium 41847027

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Maturation of mammalian H/ACA box snoRNAs: PAPD5-dependent adenylation and PARN-dependent trimming. RNA (New York, N.Y.) 134 22442037
2018 Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation. Science (New York, N.Y.) 130 30026317
2014 PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease. Proceedings of the National Academy of Sciences of the United States of America 129 25049417
2020 Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells. Cell stem cell 78 32320679
2019 PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization. Hepatology (Baltimore, Md.) 74 30365161
2011 PAPD5, a noncanonical poly(A) polymerase with an unusual RNA-binding motif. RNA (New York, N.Y.) 74 21788334
2020 Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita. Blood advances 36 32559291
2019 Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita. Blood 31 30728146
2020 The Dihydroquinolizinone Compound RG7834 Inhibits the Polyadenylase Function of PAPD5 and PAPD7 and Accelerates the Degradation of Matured Hepatitis B Virus Surface Protein mRNA. Antimicrobial agents and chemotherapy 27 33046485
2021 Host Poly(A) Polymerases PAPD5 and PAPD7 Provide Two Layers of Protection That Ensure the Integrity and Stability of Hepatitis B Virus RNA. Journal of virology 23 34191584
2016 HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5. Scientific reports 18 27752128
2020 Long noncoding RNA CASC2 inhibits ox-LDL-mediated vascular smooth muscle cells proliferation and migration via the regulation of miR-532-3p/PAPD5. Molecular medicine (Cambridge, Mass.) 9 32698757
2021 The EIF4E1-4EIP cap-binding complex of Trypanosoma brucei interacts with the terminal uridylyl transferase TUT3. PloS one 7 34807934
2025 Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5. Nature communications 3 40204699
2026 Primer- and template-independent RNA polymerization by terminal nucleotidyltransferase TENT4B. bioRxiv : the preprint server for biology 0 41847027

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