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Showing NUDT21 — CPSF5 is a alias.

NUDT21

Cleavage and polyadenylation specificity factor subunit 5 · UniProt O43809

Length
227 aa
Mass
26.2 kDa
Annotated
2026-06-10
75 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUDT21 (CFIm25/CPSF5) is the RNA-binding subunit of the Cleavage Factor Im complex and a master regulator of alternative polyadenylation (APA) that shapes 3'UTR length genome-wide (PMID:24814343, PMID:29249356). It is the first Nudix-fold protein shown to bind RNA sequence-specifically, recognizing UGUA elements through a defined base-pairing geometry while retaining no detectable hydrolase activity, and its RNA binding is mutually exclusive with the signaling metabolite Ap4A (PMID:20479262). By promoting distal poly(A) site usage, NUDT21 lengthens 3'UTRs to expose miRNA-binding sites and enhance AGO2-dependent silencing, whereas its depletion shifts processing to proximal sites, shortens 3'UTRs, and elevates proliferative and oncogenic protein output across glioblastoma, hepatocellular, bladder, and renal cancers (PMID:24814343, PMID:28964783, PMID:29780166, PMID:37737260). The protein partners with CPSF6/CFIm68 to assemble the functional complex (PMID:32431549, PMID:40425546), and can be redirected to specific transcripts by RNA-modification readers and other RNA-binding proteins including IGF2BP3 (m6A) and FXR1 (PMID:35194031, PMID:40301554). NUDT21 abundance and activity are tuned by post-translational control: TRIM65-mediated K48-linked ubiquitination at K56 targets it for proteasomal degradation (PMID:38951701), PRMT7-deposited mono-methylation at K23 (erased by HDAC2) restrains its oncogenic APA program (PMID:39208673), and AARS1-catalyzed lactylation at K23 enhances CPSF6 binding and complex assembly (PMID:40425546). Beyond canonical 3' processing, NUDT21 directs differential polyadenylation of chromatin regulators during reprogramming and cell-fate transitions (PMID:29249356), and complete loss shortens 3'UTRs of nuclear pore and other complex subunits, impairing co-translational complex assembly and triggering proteotoxic stress and cell cycle arrest (PMID:41580420). Reduced NUDT21 dosage produces tissue-level phenotypes including learning deficits and cortical hyperexcitability in mice and exaggerated fibrosis, while elevated dosage lowers MeCP2 protein via MECP2 3'UTR APA, linking NUDT21 to neurodevelopmental and fibrotic disease (PMID:26312503, PMID:31757866, PMID:32319885).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2010 High

    Established the structural basis for how an APA factor reads pre-mRNA: it answered how CFIm25 achieves sequence-specific RNA recognition despite belonging to a hydrolase fold.

    Evidence Crystal structures of CFIm25-UGUA RNA complexes with mutational and in vitro binding analysis

    PMID:20479262

    Open questions at the time
    • Did not establish how UGUA recognition translates into poly(A) site selection in cells
    • Physiological relevance of Ap4A competition not demonstrated in vivo
  2. 2014 High

    Defined NUDT21's genome-wide function as a repressor of proximal poly(A) site usage and connected 3'UTR shortening to oncogenic transformation.

    Evidence Genome-wide APA RNA-seq after siRNA knockdown plus glioblastoma xenograft assays

    PMID:24814343

    Open questions at the time
    • Did not resolve which shortened transcripts drive tumorigenicity
    • Mechanism of distal-site preference not structurally linked to the 2010 binding model
  3. 2015 High

    Showed NUDT21 dosage controls a specific disease-relevant target, MeCP2, via APA, providing a gene-dosage mechanism for neurodevelopmental phenotypes.

    Evidence Patient-derived lymphoblast APA analysis with siRNA rescue normalizing MeCP2

    PMID:26312503

    Open questions at the time
    • Did not test whether NUDT21 manipulation reverses neuronal phenotypes
    • Causal NUDT21 mutation in patients not established here
  4. 2017 High

    Demonstrated NUDT21-directed APA controls cell fate by tuning chromatin regulator protein levels, extending its role beyond cancer to developmental reprogramming.

    Evidence Reprogramming screen with RNA-seq, proteomics, and chromatin-regulator knockdown epistasis

    PMID:29249356

    Open questions at the time
    • Did not identify the full set of fate-determining target transcripts
    • Upstream regulation of NUDT21 during reprogramming unresolved
  5. 2017 Medium

    Linked NUDT21-mediated 3'UTR lengthening mechanistically to enhanced miRNA silencing by increasing AGO2-mRNA engagement.

    Evidence Co-IP, immunofluorescence co-localization in P/GW bodies, and AGO2-mRNA binding assays

    PMID:28964783

    Open questions at the time
    • Single lab, co-localization-based
    • Direct vs. indirect effect on AGO2 loading not separated
  6. 2018 Medium

    Identified specific APA targets (PSMB2, CXXC5; GLS isoforms) showing how individual transcript-level changes produce cancer phenotypes and metabolic rewiring.

    Evidence Global APA profiling with target validation and functional rescue knockdowns in HCC and cancer cells

    PMID:27095025 PMID:29780166

    Open questions at the time
    • MAPK/PTEN signaling links (PMID 30349365) remain correlative
    • Direct NUDT21 binding to these target 3'UTRs not all demonstrated
  7. 2020 High

    Extended NUDT21's APA function to fibrosis and neuronal disease using in vivo models, establishing dosage-sensitive organismal phenotypes.

    Evidence Fibroblast-specific conditional knockout (skin fibrosis) and Nudt21+/- mice with behavioral and electrophysiology readouts plus human neuron APA profiling

    PMID:31757866 PMID:32319885

    Open questions at the time
    • Causal target transcripts for each phenotype not fully defined
    • Therapeutic reversibility not tested
  8. 2020 Medium

    Revealed non-canonical roles connecting NUDT21 to antiviral signaling and to negative regulation of its complex partner CPSF6.

    Evidence Co-IP and localization with IPS-1/stress granules; mass spectrometry and CPSF6 knockdown rescue in breast cancer

    PMID:32431549 PMID:33219146

    Open questions at the time
    • Mechanism of NUDT21 mitochondrial localization unclear
    • How NUDT21 negatively regulates CPSF6 expression not defined
  9. 2022 Medium

    Showed NUDT21 participates in alternative 3' processing complexes beyond canonical CFIm, broadening its compositional repertoire.

    Evidence Reciprocal co-IP and mass spectrometry identifying an FXR1-CFIm25/CFIm68 complex with TRAF1 processing readout

    PMID:35194031

    Open questions at the time
    • Stoichiometry and structural arrangement of the FXR1-CFIm complex unknown
    • Generality beyond TRAF1 untested
  10. 2023 Medium

    Established post-transcriptional and condensate-based control of NUDT21, including sequestration by PABPN1 aggregates and E3-ligase-driven destabilization.

    Evidence Phase-transition assays (PABPN1 sequestration) and co-IP/ubiquitination/stability assays with TRIP12 and LINC00921

    PMID:37422193 PMID:37999979

    Open questions at the time
    • TRIP12 ubiquitination site on NUDT21 not mapped here
    • Physiological contexts of sequestration not defined
  11. 2023 Medium

    Implicated NUDT21/CPSF5 in viral biology through HIV-1-induced CPSF6/CPSF5 nuclear condensates required for productive infection.

    Evidence Immunofluorescence, condensate disruption (1,6-hexanediol), and HIV-1 capsid mutant infection in T cells and macrophages

    PMID:37414787

    Open questions at the time
    • Molecular function of CPSF5 within the condensate not defined
    • Whether APA activity is required is unknown
  12. 2024 High

    Mapped writer/eraser PTM control of NUDT21 stability and activity, defining how ubiquitination and methylation tune its oncogenic APA program.

    Evidence TRIM65 K48-ubiquitination at K56 (site-mapped, in vivo AAV) and PRMT7 mono-methylation at K23 with HDAC2 eraser (knockin mice, metabolomics)

    PMID:38951701 PMID:39208673

    Open questions at the time
    • Crosstalk between K23 and K56 modifications not resolved
    • Upstream signals controlling these writers in disease unclear
  13. 2025 High

    Showed metabolic lactylation of NUDT21 directly enhances CFIm complex assembly, linking cellular lactate to APA-mediated drug resistance.

    Evidence K23 lactylation mapping, AARS1 writer/HDAC2 eraser, co-IP showing enhanced CPSF6 binding, FDX1 3'UTR reporter and in vivo tumor models

    PMID:40425546

    Open questions at the time
    • Quantitative contribution of lactylation versus methylation at the shared K23 not resolved
    • Generality across tumor types untested
  14. 2025 Medium

    Demonstrated that RNA modifications and reader proteins recruit NUDT21 to specific transcripts, providing transcript-selective targeting mechanisms in cancer and infection.

    Evidence IGF2BP3-NUDT21 (m6A, SPTBN1), NAT10/ac4C-directed CPSF5 binding (viral RNA), and Mtb-induced disruption of NUDT21-CPSF6 (FTH1) via co-IP and APA profiling

    PMID:40167508 PMID:40301554 PMID:40384984

    Open questions at the time
    • Whether modification readers compete with intrinsic UGUA recognition unclear
    • Single-lab studies per target
  15. 2025 Medium

    Defined NUDT21 as a driver of macrophage differentiation and polarization through APA of NF-kB and AKT2 transcripts, with its own translation gated by APA/PCBP1.

    Evidence APA profiling and target knockdown epistasis (TAB2, TBL1XR1), ASO blocking of AKT2 proximal poly(A) site, and PCBP1-long-3'UTR RIP in monocytes

    PMID:40022203 PMID:41830116 PMID:42111214

    Open questions at the time
    • In vivo relevance in macrophage biology not fully established
    • Feedback between NUDT21's own APA and its activity not quantified
  16. 2026 High

    Revealed that complete NUDT21 loss disrupts co-translational assembly of protein complexes via 3'UTR shortening of nucleoporin mRNAs, defining a proteostasis function distinct from differentiation control, and uncovered a chromatin/transcription role with lineage transcription factors.

    Evidence Graded knockdown with APA profiling, CRISPR deletion of individual nucleoporin 3'UTRs recapitulating phenotypes, co-translational assembly assays (PMID 41580420); ChIP and TF co-IP plus pharmacological degradation in T-ALL (PMID 41926643)

    PMID:41580420 PMID:41926643

    Open questions at the time
    • How 3'UTR length controls co-translational assembly mechanistically not fully resolved
    • Direct vs. indirect basis of chromatin/promoter localization unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple K23 modifications (methylation, lactylation) and K56 ubiquitination are integrated to set NUDT21 activity and APA output in different cell states remains unresolved, as does the structural basis by which distal versus proximal site choice is encoded.
  • No unified model linking PTM state to genome-wide APA direction
  • No structural model of the full CFIm-NUDT21-CPSF6 complex on substrate
  • Mechanism of proximal vs. distal site selection in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
AARS1CPSF6FXR1IGF2BP3IPS-1PRMT7TRIM65TRIP12
Complex memberships
Cleavage Factor Im (CFIm)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Crystal structures of human CFIm25 homodimer in complex with UGUAAA and UUGUAU RNA sequences revealed that CFIm25 is the first Nudix protein to bind RNA in a sequence-specific manner. The UGUA sequence contributes binding specificity through an intramolecular G:A Watson-Crick/sugar-edge base interaction. Mutational data suggested a mechanism for simultaneous recognition of two UGUA elements. CFIm25 has no detectable hydrolase activity despite its Nudix fold. The signaling molecule Ap4A (diadenosine tetraphosphate) and RNA bind CFIm25 in a mutually exclusive manner, suggesting small-molecule regulation of mRNA 3' processing. Crystal structure determination, mutational analysis, in vitro binding assays Proceedings of the National Academy of Sciences of the United States of America High 20479262
2014 CFIm25 (NUDT21) acts as a broad repressor of proximal poly(A) site usage. CFIm25 knockdown causes 3' UTR shortening of at least 1,450 genes (11% of expressed mRNAs), increases cell proliferation, and upregulates oncogenes including cyclin D1. Downregulation of CFIm25 in glioblastoma cells enhances tumorigenic properties and increases tumor size; overexpression reduces these properties and inhibits tumor growth. RNA-seq with regression model for APA analysis, CFIm25 siRNA knockdown, glioblastoma xenograft tumor assays Nature High 24814343
2015 NUDT21 regulates MeCP2 protein quantity via alternative polyadenylation. Elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3' UTR, resulting in enrichment of inefficiently translated long mRNA isoforms and reduced MeCP2 protein. siRNA-mediated knockdown of NUDT21 in duplication patient lymphoblasts restores MeCP2 to normal levels. Patient-derived lymphoblastoid cell analysis, MECP2 mRNA and protein abundance measurement, siRNA knockdown eLife High 26312503
2016 CFIm25 depletion causes a shift to proximal poly(A) site usage within the KGA isoform of glutaminase (GLS) 3' UTR and alters splicing to exclude the GAC 3' UTR. The apoptosis induced by downregulation of the GAC isoform can be alleviated through concurrent reduction in CFIm25 expression, linking CFIm25 to glutamine metabolism in cancer cells. CFIm25 siRNA depletion, RT-PCR for isoform analysis, apoptosis assays, concurrent knockdown rescue experiments RNA (New York, N.Y.) Medium 27095025
2017 Nudt21 directs differential polyadenylation of over 1,500 transcripts during cellular reprogramming to pluripotency, with the resulting protein-level changes strongly enriched for chromatin regulators. Suppression of these chromatin regulator proteins neutralizes the effect of Nudt21 during reprogramming, establishing a direct link between alternative polyadenylation and chromatin signaling in cell fate control. Transcription-factor-induced reprogramming screen, RNA-seq, proteomic analysis, epistasis via chromatin regulator knockdown Cell High 29249356
2017 NUDT21 co-localizes with AGO2 in P/GW bodies in normal liver cells, and this co-localization is diminished in cancer cells. NUDT21 elongates the 3' UTR of mRNAs and enhances the efficiency of miRNA-mediated gene silencing by increasing AGO2-mRNA binding efficiency. Co-immunoprecipitation, immunofluorescence co-localization, AGO2-mRNA binding assays, NUDT21 knockdown/overexpression Cancer letters Medium 28964783
2018 NUDT21 knockdown in K562 cells inhibits proliferation and promotes apoptosis through the MAPK/ERK pathway, involving modulation of PTEN and downstream ERK1/2 signaling. Lentiviral NUDT21 knockdown in K562 cells, RNA microarray, intracellular signaling array, western blotting, flow cytometry Cancer management and research Low 30349365
2018 NUDT21 knockdown increases proximal polyadenylation site usage in the 3' UTRs of PSMB2 and CXXC5, resulting in marked increases in their protein expression, which promote HCC cell proliferation and invasion. Global APA site profiling, NUDT21 knockdown/overexpression, western blotting for PSMB2 and CXXC5, functional rescue knockdown of PSMB2 and CXXC5 Oncogene Medium 29780166
2018 CFIm25 inhibits HCC cell migration and invasion by blocking the p38 and JNK/c-Jun signaling pathways, and disrupts epithelial-mesenchymal transition by increasing E-cadherin. CFIm25 knockdown increases transcriptional activity of AP-1. CFIm25 knockdown/overexpression, in vitro invasion and migration assays, in vivo metastasis models, western blotting for EMT markers and MAPK pathway components, AP-1 reporter assay Oncotarget Medium 29545935
2019 NUDT21 promotes circRNA cyclization by recognizing UGUA sequences, and NUDT21 knockdown disrupts circRNA-miRNA-mRNA ceRNA pathways in hepatocellular carcinoma. Overexpression of downregulated circRNAs assists NUDT21-mediated tumor suppression. NUDT21 knockdown/overexpression, circRNA expression profiling, UGUA motif mutagenesis, ceRNA pathway analysis, functional rescue with circRNA overexpression Oncogene Medium 31570791
2019 NUDT21 modulates the expression of ANXA2 and LIMK2 via alternative polyadenylation in bladder cancer, and these genes act in the Wnt/β-catenin and NF-κB signaling pathways. Global APA site profiling, NUDT21 knockdown/overexpression, TOP/FOP flash reporter assay (Wnt/β-catenin), western blotting Theranostics Medium 31695759
2020 CFIm25 depletion promotes 3' UTR shortening of TGFβ-regulated fibrotic genes and enhances their protein expression in normal dermal fibroblasts. Fibroblast-specific CFIm25 deletion in mice exaggerates bleomycin-induced skin fibrosis, and CFIm25 restoration attenuates this fibrosis. CFIm25 knockdown in fibroblasts, APA profiling, fibroblast-specific conditional knockout mice, bleomycin-induced fibrosis model The Journal of experimental medicine High 31757866
2020 Nudt21+/- mice with 30% reduced CFIm25 protein show learning deficits, cortical hyperexcitability, and misregulated APA in hippocampi. Partial NUDT21 inhibition (30% CFIm25 reduction) in human stem cell-derived neurons induces APA and protein level misregulation in hundreds of genes, several of which cause intellectual disability when mutated. Nudt21+/- mouse model, behavioral testing (learning), electrophysiology (cortical hyperexcitability), APA profiling in hippocampi, human stem cell-derived neuron experiments eLife High 32319885
2020 NUDT21 co-localizes with EZH2 in human trophoblast cells and binds to EZH2 mRNA. NUDT21 elongates 3' UTRs, exposing additional miRNA binding sites (including miR138 and miR363), thereby enhancing miRNA-mediated silencing of EZH2. RNA immunoprecipitation (RIP), immunofluorescence co-localization, NUDT21 loss-of-function assays, 3' UTR length analysis Journal of cellular and molecular medicine Low 30883033
2020 NUDT21 physically associates with IPS-1 (mitochondrial antiviral adaptor) and mediates IPS-1 localization to stress granules in response to poly(I:C) transfection. A fraction of NUDT21 localizes to mitochondria in resting cells and moves to stress granules upon viral dsRNA stimulation. NUDT21 is required for efficient type I IFN induction in response to viral infection. Co-immunoprecipitation, immunofluorescence/subcellular fractionation, poly(I:C) stimulation, NUDT21 knockdown in HeLa and RAW264.7 cells, IFN induction assays Journal of immunology Medium 33219146
2020 HIF-1α-mediated downregulation of NUDT21 alters expression patterns of the two GLS1 isoforms GAC and KGA in SCLC under hypoxia, linking hypoxic tumor environments to aberrant glutamine metabolism. NUDT21 shRNA transduction, hypoxia treatment, HIF-1α inhibition, isoform expression analysis by RT-PCR/western blot Biochemical and biophysical research communications Low 32228887
2020 NUDT21 directly interacted with CPSF6 as detected by mass spectrometry and western blotting, and negatively regulated CPSF6 expression in breast cancer cells. Knockdown of CPSF6 reversed NUDT21 expression-induced cancer cell migration and invasion. Mass spectrometry, western blotting, co-immunoprecipitation, CPSF6 knockdown rescue experiments Cancer management and research Medium 32431549
2021 NUDT21 gene editing in human embryonic stem cells impairs differentiation potential and increases proliferation, but unexpectedly did not significantly affect cellular mRNA 3' processing efficiency or APA profile. Instead, CFIm25 perturbation affects RNA polymerase II occupancy at the body of transcribed genes and promotes expression of transcripts associated with proliferation/differentiation including rex1. CRISPR/Cas9 editing of CFIm25 in hESCs, RNA-seq APA profiling, Pol II ChIP-seq, proliferation and differentiation assays RNA biology Medium 35491945
2022 FXR1 interacts with CFIm25 (NUDT21) and CFIm68, forming a novel 3' processing machinery for sequence-specific poly(A) site recognition. This FXR1-CFIm25/CFIm68 complex affects 3' processing of TRAF1 mRNA, leading to its nuclear stabilization. Co-immunoprecipitation, mass spectrometry, 3' end processing assays, TRAF1 mRNA stability analysis Cell death & disease Medium 35194031
2023 Poly(A)-binding protein nuclear 1 (PABPN1) aggregates sequester CFIm25 in an mRNA-dependent manner, impairing CFIm25 function in alternative polyadenylation. Ala expansion drives PABPN1 aggregation from nuclear speckles, and poly(A) nucleotide is essential for early-stage condensation. Biochemical phase transition assays, molecular cell biology, immunofluorescence, APA profiling in PABPN1 aggregate conditions The Journal of biological chemistry Medium 37422193
2023 LINC00921 lncRNA controls NUDT21 protein stability by facilitating binding of NUDT21 with the E3 ubiquitin ligase TRIP12, leading to NUDT21 destabilization and subsequent 3' UTR shortening of MED23 mRNA via APA. Co-immunoprecipitation, ubiquitination assays, APA profiling, NUDT21 stability assays with TRIP12 knockdown/overexpression Cell reports Medium 37999979
2023 NUDT21 loss (induced by DNMT3B-mediated promoter methylation) causes 3' UTR shortening of MORC2 mRNA, stabilizing MORC2 and enhancing its oncogenic activity in kidney renal clear cell carcinoma. MORC2 subsequently recruits DNMT3A to hypermethylate the DAPK1 promoter, silencing this tumor suppressor. APA profiling, NUDT21 promoter methylation analysis, MORC2 3'UTR reporter assay, DNMT3A ChIP, DAPK1 promoter methylation assay JCI insight Medium 37737260
2023 NUDT21 knockdown in glioma cells causes 3' UTR shortening of LAMC1, removing miR-124/506 binding sites and relieving miRNA repression, resulting in increased LAMC1 protein and enhanced glioma cell migration. Co-depletion of LAMC1 with NUDT21 abolishes the NUDT21-knockdown-induced migration phenotype. PAC-seq APA profiling, qRT-PCR, western blotting for LAMC1, miRNA binding site analysis, co-depletion epistasis experiment, cell migration assays Journal of neuro-oncology Medium 37389756
2023 HIV-1 nuclear entry triggers translocation of CPSF6 from paraspeckles into nuclear speckles, forming biomolecular condensates. CPSF5 (NUDT21), but not CPSF7, co-localizes with CPSF6 in these condensates. Formation of CPSF6/CPSF5 condensates does not require HIV-1 integration or reverse transcription, but is required for productive wild-type HIV-1 infection (not for capsid mutants N74D/A77V that do not form condensates). Immunofluorescence, osmotic stress/1,6-hexanediol condensate disruption assays, HIV-1 infection with capsid mutants, fluorescence microscopy in T cells and primary macrophages Scientific reports Medium 37414787
2024 TRIM65 E3 ligase interacts with NUDT21 (identified by yeast-hybrid screen) and induces K48-linked polyubiquitination of NUDT21 at lysine 56, leading to proteasomal degradation. NUDT21 degradation inhibits TGF-β1-mediated SMAD and ERK1/2 signaling and alters 3'UTR-APA of pro-fibrotic genes (Col1a1, Fn-1, Tgfbr1, Wnt5a, Fzd2). Yeast-hybrid screen, co-immunoprecipitation, ubiquitination assay with K48-linkage specificity, proteasome inhibitor treatment, APA profiling, AAV9-mediated NUDT21 knockdown in vivo Cell death and differentiation High 38951701
2024 PRMT7-mediated mono-methylation of NUDT21 (at K23) induces a shift in 3'UTR usage, reducing oncogenicity in prostate cancer. Un-methylated NUDT21 promotes cancer growth and cuproptosis insensitivity by suppressing docosahexaenoic acid (DHA) biosynthesis. HDAC2 serves as the eraser of NUDT21 K23 mono-methylation. Mono-methylation monoclonal antibody generation, conditional knockin transgenic mouse model, transcriptomic and metabolomic analyses, loss-of-function and gain-of-function assays, drug-resistant cell lines Drug resistance updates High 39208673
2025 L-lactate-induced lactylation of NUDT21 at K23 (catalyzed by AARS1 as the 'writer' and removed by HDAC2 as the 'eraser') enhances NUDT21 interaction with CPSF6, facilitating CFIm complex formation and inducing 3'UTR lengthening of FDX1. This extended FDX1 3'UTR attenuates FDX1 protein output, conferring resistance to cuproptosis in esophageal squamous cell carcinoma. Lactylation site mapping (K23), co-immunoprecipitation for NUDT21-CPSF6 interaction, APA profiling, FDX1 3'UTR reporter assay, AARS1 and HDAC2 functional validation, in vivo tumor models Cell discovery High 40425546
2025 IGF2BP3 interacts with NUDT21 (recognizing m6A-modified site in intron 32 of SPTBN1), recruiting NUDT21 to promote usage of the SPTBN1 proximal polyadenylation site and increasing generation of short SPTBN1 transcripts in ovarian cancer cells. Co-immunoprecipitation, m6A site mapping, APA site profiling, SPTBN1 isoform functional assays Communications biology Medium 40301554
2025 N-acetyltransferase 10 (NAT10) catalyzes ac4C modification at nucleotide 3311 of MVC viral RNA, which promotes specific binding of CPSF5 (NUDT21) to the target region. NP1 recruits CPSF5 to MVC RNAs in an ac4C-dependent manner, and this CPSF5 binding is required for precise alternative viral RNA processing without altering RNA stability. acRIP-seq, RedaC:T-seq for ac4C site mapping, in vitro binding assays, NP1/CPSF5 co-IP, viral RNA processing assays with ac4C mutants Nucleic acids research Medium 40167508
2025 PCBP1 suppresses CFIm25 (NUDT21) translation in monocytes by binding to its long 3'UTR. During monocyte-to-macrophage differentiation, alternative polyadenylation generates a shorter CFIm25 3'UTR lacking PCBP1 binding sites, releasing translational suppression and increasing CFIm25 protein. PCBP1 knockdown increases CFIm25 protein and induces macrophage differentiation markers without stimulation. RNA immunoprecipitation (PCBP1-long 3'UTR), ribosome association analysis, APA analysis during differentiation, PCBP1 knockdown experiments FEBS letters Medium 41830116
2025 CFIm25 (NUDT21) promotes macrophage differentiation by inducing APA-mediated 3'UTR shortening of TAB2 and TBL1XR1 mRNAs (positive NF-κB regulators), increasing their protein levels and activating NF-κB signaling. CFIm25 overexpression elevates NF-κB-p65 phosphorylation and increases expression of NF-κB targets. Knockdown of TAB2 and TBL1XR1 in CFIm25-overexpressing cells attenuates these effects. CFIm25 overexpression/knockdown in monocytic cell lines, 3' end-focused sequencing (APA), western blotting, NF-κB chemical inhibition, TAB2/TBL1XR1 knockdown epistasis Cell communication and signaling Medium 40022203
2025 CFIm25 promotes proximal polyadenylation of AKT2 mRNA, generating shorter transcripts with enhanced stability and translational efficiency that increase Akt2 protein levels and support M1 macrophage polarization via NF-κB signaling. Blocking the proximal AKT2 poly(A) site with an antisense oligonucleotide reduces Akt2 expression and M1 traits. CFIm25 overexpression/knockdown, APA site analysis of AKT2, ASO blocking of proximal poly(A) site, Akt2 protein and mRNA stability analysis, nitric oxide/CD80/cytokine assays for macrophage polarization iScience Medium 42111214
2026 NUDT21 promotes distal poly(A) site usage of UBE2D3 oncogenic transcripts in T-ALL, generating long 3'UTR isoforms with enhanced mRNA stability and increased protein expression. NUDT21 also localizes to transcriptionally active promoters and interacts with lineage-specific transcription factors MYB, RUNX1, and GATA3 to facilitate MYC transcription. Pharmacological targeting with ouabain octahydrate degrades NUDT21 protein and suppresses UBE2D3 and MYC. Multi-omics analysis, APA profiling, ChIP/chromatin localization, co-IP with transcription factors, pharmacological NUDT21 degradation, T-ALL functional assays Advanced science Medium 41926643
2026 Moderate Nudt21 suppression causes maturation arrest of stem cells due to 3'UTR-shortening of differentiation-associated mRNAs that escape miRNA regulation and perturb ceRNA networks. Complete Nudt21 suppression additionally shortens 3'UTRs of mRNAs encoding nuclear pore complex subunits, leading to complex destabilization, proteotoxic stress, DNA damage, and cell cycle arrest. Deletion of alternative 3'UTRs of individual nucleoporins recapitulates defects of Nudt21 loss, and co-translational assembly of dozens of protein complexes is impaired in Nudt21-deficient cells. Graded Nudt21 knockdown, APA profiling, nuclear pore complex stability assays, proteotoxic stress markers, individual nucleoporin 3'UTR deletion by CRISPR, ribosome profiling/co-translational assembly analysis Nature communications High 41580420
2024 NUDT21 promotes usage of the proximal polyadenylation site on MZT1 mRNA by binding to the UGUA element located upstream of the proximal PAS in pancreatic cancer cells. APA profiling, UGUA element analysis, NUDT21 binding site mapping, functional studies with proximal PAS usage iScience Low 38303721
2024 NUDT21 mediates APA of LOXL2 3'UTR, thereby modulating LOXL2 expression and ECM protein cross-linking in silica-induced pulmonary fibrosis. NUDT21 modulation, APA analysis of LOXL2 3'UTR, siRNA-loaded liposomes for in vivo LOXL2 knockdown Ecotoxicology and environmental safety Low 39700768
2025 Mycobacterium tuberculosis disrupts the interaction between NUDT21 and CPSF6, impairing NUDT21's ability to bind UGUA motifs in the FTH1 3'UTR. This shifts polyadenylation toward longer FTH1 isoforms with enhanced protein synthesis, facilitating bacterial survival. Silencing NUDT21 reduces macrophage bactericidal activity against Mtb. Co-immunoprecipitation (NUDT21-CPSF6 interaction), APA profiling of FTH1, NUDT21 knockdown, intracellular Mtb survival assays Frontiers in cellular and infection microbiology Medium 40384984
2025 miR-23a, miR-222, and miR-323a directly regulate NUDT21 mRNA levels in mantle cell lymphoma cells. The NUDT21 pre-mRNA undergoes alternative polyadenylation within the same terminal exon generating three different sized mRNAs with different 3'UTR lengths, each using a different canonical polyadenylation signal (AAUAAA). The different 3'UTR lengths affect NUDT21's own evasion of miRNA regulation. miRNA mimic and inhibitor experiments, 3'UTR luciferase reporter assays, mRNA stability measurements, APA isoform characterization FASEB journal Medium 39812508

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 362 24814343
2010 Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3' processing. Proceedings of the National Academy of Sciences of the United States of America 131 20479262
2017 Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. Cell 106 29249356
2019 NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. Oncogene 102 31570791
2018 NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene 91 29780166
2015 NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife 65 26312503
2017 NUDT21 regulates 3'-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. Cancer letters 64 28964783
2019 NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation. Theranostics 54 31695759
2016 CFIm25 regulates glutaminase alternative terminal exon definition to modulate miR-23 function. RNA (New York, N.Y.) 40 27095025
2020 Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation. The Journal of experimental medicine 36 31757866
2020 Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation. eLife 31 32319885
2021 Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation. Oncogene 30 33619322
2016 MicroRNA-181a promotes proliferation and inhibits apoptosis by suppressing CFIm25 in osteosarcoma. Molecular medicine reports 30 27633853
2019 CFIm25 and alternative polyadenylation: Conflicting roles in cancer. Cancer letters 28 31181319
2022 The emerging roles of CFIm25 (NUDT21/CPSF5) in human biology and disease. Wiley interdisciplinary reviews. RNA 27 35965101
2017 Silencing NUDT21 Attenuates the Mesenchymal Identity of Glioblastoma Cells via the NF-κB Pathway. Frontiers in molecular neuroscience 25 29311812
2023 Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. Scientific reports 23 37414787
2018 Knockdown of NUDT21 inhibits proliferation and promotes apoptosis of human K562 leukemia cells through ERK pathway. Cancer management and research 22 30349365
2025 NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance. Cell discovery 21 40425546
2022 FXR1 can bind with the CFIm25/CFIm68 complex and promote the progression of urothelial carcinoma of the bladder by stabilizing TRAF1 mRNA. Cell death & disease 20 35194031
2020 Involved microRNAs in alternative polyadenylation intervene in breast cancer via regulation of cleavage factor "CFIm25". Scientific reports 19 32665581
2018 CFIm25 inhibits hepatocellular carcinoma metastasis by suppressing the p38 and JNK/c-Jun signaling pathways. Oncotarget 19 29545935
2024 TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative polyadenylation. Cell death and differentiation 17 38951701
2024 Un-methylation of NUDT21 represses docosahexaenoic acid biosynthesis contributing to enzalutamide resistance in prostate cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 17 39208673
2020 CFIm25-regulated lncRNA acv3UTR promotes gastric tumorigenesis via miR-590-5p/YAP1 axis. Oncogene 17 32066878
2023 Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis. JCI insight 16 37737260
2020 NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing. Biochemical and biophysical research communications 16 32228887
2021 NUDT21 Promotes Tumor Growth and Metastasis Through Modulating SGPP2 in Human Gastric Cancer. Frontiers in oncology 15 34660260
2020 NUDT21 Suppresses Breast Cancer Tumorigenesis Through Regulating CPSF6 Expression. Cancer management and research 15 32431549
2020 miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer. Bioscience reports 15 32816024
2024 Nudt21-mediated alternative polyadenylation of MZT1 3'UTR contributes to pancreatic cancer progression. iScience 14 38303721
2024 A novel spherical GelMA-HAMA hydrogel encapsulating APET×2 polypeptide and CFIm25-targeting sgRNA for immune microenvironment modulation and nucleus pulposus regeneration in intervertebral discs. Journal of nanobiotechnology 14 39267105
2023 LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation. Cell reports 13 37999979
2020 Nudt21-mediated alternative polyadenylation of HMGA2 3'-UTR impairs stemness of human tendon stem cell. Aging 13 32979259
2017 Silencing the cleavage factor CFIm25 as a new strategy to control Entamoeba histolytica parasite. Journal of microbiology (Seoul, Korea) 13 28956353
2020 NUDT21 knockdown inhibits proliferation and promotes apoptosis of pancreatic ductal adenocarcinoma through EIF2 signaling. Experimental cell research 10 32707135
2015 Amino acid residues Leu135 and Tyr236 are required for RNA binding activity of CFIm25 in Entamoeba histolytica. Biochimie 10 25941172
2025 The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κB pathway. Cell communication and signaling : CCS 9 40022203
2018 Effect of CFIm25 knockout on RNA polymerase II transcription. BMC research notes 9 30547832
2024 NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis. Ecotoxicology and environmental safety 8 39700768
2023 Relationship between NUDT21 mediated alternative polyadenylation process and tumor. Frontiers in oncology 8 36816917
2023 NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. Journal of neuro-oncology 8 37389756
2019 The role of NUDT21 in microRNA-binging sites of EZH2 gene increases the of risk preeclampsia. Journal of cellular and molecular medicine 8 30883033
2024 Unraveling the role of MiR-181 in skin fibrosis pathogenesis by targeting NUDT21. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 39250282
2023 Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression. Molecular oncology 7 37356089
2025 IGF2BP3 recruits NUDT21 to regulate SPTBN1 alternative polyadenylation and drive ovarian cancer progression. Communications biology 6 40301554
2023 PABPN1 aggregation is driven by Ala expansion and poly(A)-RNA binding, leading to CFIm25 sequestration that impairs alternative polyadenylation. The Journal of biological chemistry 6 37422193
2020 CFIm25 in Solid Tumors: Current Research Progress. Technology in cancer research & treatment 6 32643564
2025 Characterization and molecular targeting of CFIm25 (NUDT21/CPSF5) mRNA using miRNAs. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 5 39812508
2024 NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis. Journal of cancer research and clinical oncology 5 38195952
2021 CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation. RNA biology 5 35491945
2020 NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense. Journal of immunology (Baltimore, Md. : 1950) 5 33219146
2025 N4-acetylcytidine coordinates with NP1 and CPSF5 to facilitate alternative RNA processing during the replication of minute virus of canines. Nucleic acids research 4 40167508
2025 Mycobacterium tuberculosis modulates NUDT21-mediated alternative polyadenylation to enhance FTH1 expression in macrophages and promotes intracellular growth. Frontiers in cellular and infection microbiology 3 40384984
2024 Pan-cancer analysis of NUDT21 and its effect on the proliferation of human head and neck squamous cell carcinoma. Aging 3 38349866
2023 NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2. Open life sciences 3 37077345
2025 CFIm25-Dependent Alternative Polyadenylation in AKT2 mRNA Programs Macrophage Polarization. bioRxiv : the preprint server for biology 2 40667110
2020 [Effect of NUDT21 on Alternative Splicing of Transcripts in K562 Cells]. Zhongguo shi yan xue ye xue za zhi 2 33067945
2025 NUDT21-mediated Alternative Polyadenylation of CDK19 Reprograms Cholesterol Biosynthesis to Drive Colorectal Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41255211
2024 Platr3/NUDT21/NF-κB Axis Mediates P. gingivalis-Suppressed Cementoblast Mineralization. Inflammation 1 38961014
2024 Involvement of oncomiRs miR-23, miR-24, and miR-27 in the regulation of alternative polyadenylation in glioblastoma via CFIm25 cleavage factor. Metabolic brain disease 1 39190234
2023 A new pathway for the transformation of AML in MDS: APA mechanism regulated by NUDT21 and RUNX1. Neoplasma 1 37498064
2026 Modulation of Nudt21 levels reveals dose-dependent roles of alternative polyadenylation in tissue regeneration. Nature communications 0 41580420
2026 Alternative polyadenylation releases PCBP1-mediated suppression of CFIm25 during macrophage differentiation. FEBS letters 0 41830116
2026 NUDT21 Drives T-Cell Acute Lymphoblastic Leukemia Through Dual Regulation of Alternative Polyadenylation and Transcriptional Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41926643
2026 Targeting NUDT21-mediated alternative polyadenylation of oncogenes ameliorates colorectal cancer malignancy and metastasis. British journal of cancer 0 42086673
2026 CFIm25-dependent alternative polyadenylation in AKT2 mRNA programs macrophage polarization. iScience 0 42111214
2026 The Alternative Polyadenylation Factor CFIm25 Orchestrates Macrophage Antibacterial Immunity by Amplifying TAB2-Mediated MAPK and NF-κB Signaling During Salmonella Infection. bioRxiv : the preprint server for biology 0 42124657
2026 Nanopore full-length sequencing reveals Nudt21 knockdown drives genome-wide 3'UTR shortening and transcriptome reprogramming in mouse hepatocytes. BMC genomics 0 42163102
2026 NUDT21 Downregulation Promotes Liver Fibrosis by Activating the PIM2-Mediated CEBPB/SLC2A1 Glycolytic Axis in Hepatic Stellate Cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 42201665
2025 Alternative Polyadenylation Releases PCBP1-Mediated Suppression of CFIm25 During Macrophage Differentiation. bioRxiv : the preprint server for biology 0 40667065
2025 NUDT21 Regulates Macrophage Cytokine Responses via Alternative Polyadenylation in ARDS. Research square 0 41282183
2024 Predictive Value of CFIm25 Expression in Peripheral Blood Monocytes for Coronary Atherosclerosis. International journal of medical sciences 0 38322593
2024 The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κβ pathway. bioRxiv : the preprint server for biology 0 39282342
2022 [Over-expression of NUDT21 inhibits the proliferation of HCT-116 colon cancer cells via blocking P53/CDK2/Rb pathway]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 35732608

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