Affinage

NUDT21

Cleavage and polyadenylation specificity factor subunit 5 · UniProt O43809

Length
227 aa
Mass
26.2 kDa
Annotated
2026-04-29
71 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUDT21 (CFIm25) is the RNA-binding subunit of the cleavage factor Im (CFIm) complex that globally directs alternative polyadenylation (APA), predominantly promoting distal poly(A) site usage to maintain long 3' UTRs and preserve miRNA-mediated post-transcriptional regulation. NUDT21 homodimerizes via a catalytically inactive Nudix-fold domain and specifically recognizes UGUA motifs in pre-mRNAs; its interaction with CPSF6 assembles the functional CFIm complex, and this interaction is modulated by post-translational modifications including TRIM65- and TRIP12-mediated K48-linked ubiquitination (targeting K56 for proteasomal degradation), PRMT7-mediated mono-methylation, and AARS1-catalyzed lactylation at K23 (both erased by HDAC2) (PMID:20479262, PMID:38951701, PMID:40425546, PMID:39208673). NUDT21 depletion causes widespread 3' UTR shortening across thousands of transcripts, de-repressing oncogenes, chromatin regulators, and fibrotic effectors, thereby driving tumorigenesis, impairing stem cell differentiation, and promoting fibrosis; conversely, its dose-dependent activity controls co-translational assembly of nuclear pore complexes and macrophage differentiation through APA of nucleoporin and NF-κB pathway transcripts (PMID:24814343, PMID:29249356, PMID:31757866, PMID:41580420, PMID:40022203). Beyond canonical APA, NUDT21 promotes circRNA biogenesis via UGUA motifs, participates in antiviral innate immunity by linking IPS-1 to stress granules for type I IFN induction, localizes to active promoters where it interacts with lineage-specific transcription factors to facilitate gene transcription, and forms biomolecular condensates with CPSF6 during HIV-1 nuclear entry (PMID:31570791, PMID:33219146, PMID:41926643, PMID:37414787).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2010 High

    Resolving how NUDT21 recognizes its RNA targets: crystal structures revealed that CFIm25 homodimerizes through a Nudix fold that lacks hydrolase activity and binds UGUA sequences via a specific intramolecular G:A base interaction, establishing the structural basis for its role in pre-mRNA 3' processing.

    Evidence Crystal structures of CFIm25–RNA complexes, active-site mutagenesis, and in vitro binding assays

    PMID:20479262

    Open questions at the time
    • No structure of the full CFIm heterotetramer (CFIm25₂–CFIm68₂) with RNA
    • Functional significance of Ap4A competitive binding unresolved in vivo
  2. 2014 High

    Establishing NUDT21 as a master regulator of 3' UTR length: genome-wide analysis showed that CFIm25 depletion shifts polyadenylation to proximal sites on >1,450 genes, shortening 3' UTRs and de-repressing oncogenes, thereby linking APA to tumorigenic proliferation.

    Evidence shRNA knockdown, RNA-seq APA regression analysis, overexpression rescue, and in vivo tumor growth assays in glioblastoma

    PMID:24814343

    Open questions at the time
    • Mechanism by which NUDT21 blocks proximal PAS recognition not fully defined
    • Relative contributions of individual UGUA sites at proximal vs. distal PAS unclear
  3. 2015 High

    Demonstrating clinical relevance of NUDT21-mediated APA: elevated NUDT21 shifts MECP2 mRNA to a longer, poorly translated isoform, and siRNA knockdown in MECP2 duplication patient cells restored normal MeCP2 protein, providing a therapeutic rationale for APA modulation in neurological disease.

    Evidence Patient-derived lymphoblastoid cells from deletion/duplication cases, siRNA knockdown, mRNA isoform and protein quantification

    PMID:26312503

    Open questions at the time
    • Whether NUDT21 modulation is viable therapeutically in neurons in vivo
    • Other APA targets contributing to disease phenotype not catalogued
  4. 2016 High

    Connecting NUDT21-APA to miRNA-mediated metabolic regulation: CFIm25 depletion shortened the glutaminase KGA 3' UTR but retained partial miR-23 regulation, revealing that APA-miRNA interplay fine-tunes glutamine metabolism gene expression.

    Evidence siRNA depletion, 3' RACE, luciferase 3' UTR reporters, apoptosis assays

    PMID:27095025

    Open questions at the time
    • Quantitative contribution of individual miRNA sites in shortened vs. full-length UTR not resolved
  5. 2017 High

    Linking NUDT21-controlled APA to cell fate through chromatin regulation: Nudt21 suppression altered APA of >1,500 transcripts during reprogramming, enriched for chromatin regulators, and epistasis experiments showed these chromatin targets mediated the cell fate effect, establishing APA as an upstream regulator of chromatin signaling.

    Evidence shRNA screen during iPSC reprogramming, APA profiling, proteomics, epistatic knockdown of individual chromatin regulators

    PMID:29249356

    Open questions at the time
    • Identity of the critical chromatin regulators whose APA changes are necessary vs. sufficient not fully delineated
    • Whether APA-driven chromatin changes are reversible upon NUDT21 restoration
  6. 2018 Medium

    Identifying specific downstream APA effectors of NUDT21 in cancer: NUDT21 knockdown shortened 3' UTRs of PSMB2 and CXXC5, increasing their protein levels and driving HCC proliferation, illustrating how individual APA targets mediate NUDT21's tumor-suppressive function.

    Evidence 3' READS APA profiling, NUDT21 knockdown/overexpression, epistatic depletion of PSMB2/CXXC5

    PMID:29780166

    Open questions at the time
    • Whether PSMB2/CXXC5 are universally affected across HCC subtypes
    • Contribution of additional APA targets not assessed
  7. 2019 Medium

    Expanding NUDT21's RNA processing role beyond linear mRNAs: NUDT21 promotes circRNA biogenesis through UGUA motifs, and its depletion reduces circRNA levels in hepatocellular carcinoma, revealing a functional connection between CFIm-mediated RNA recognition and back-splicing.

    Evidence NUDT21 knockdown/overexpression, divergent PCR for circRNA quantification, UGUA motif mutagenesis in circRNA reporters

    PMID:31570791

    Open questions at the time
    • Direct mechanism by which UGUA-bound NUDT21 facilitates back-splicing not structurally defined
    • Genome-wide scope of circRNA regulation by NUDT21 not established
  8. 2020 High

    Multiple studies revealed NUDT21's physiological importance in vivo: Nudt21 haploinsufficiency in mice causes learning deficits and cortical hyperexcitability with APA dysregulation in hippocampus, while fibroblast-specific knockout exacerbates skin fibrosis through 3' UTR shortening of TGFβ-regulated genes, and NUDT21 was found to bridge IPS-1 to stress granules for type I IFN induction during viral infection.

    Evidence Nudt21+/- mouse behavioral/EEG analysis with PAC-seq (PMID:32319885); conditional fibroblast KO plus bleomycin fibrosis model (PMID:31757866); co-IP of NUDT21–IPS-1 with subcellular fractionation and viral infection assays (PMID:33219146)

    PMID:31757866 PMID:32319885 PMID:33219146

    Open questions at the time
    • Whether neurological phenotype is purely APA-dependent or involves transcriptional roles
    • Structural basis for NUDT21–IPS-1 interaction unknown
    • Whether fibrosis phenotype involves APA-independent NUDT21 functions
  9. 2021 Medium

    Evidence emerged for an APA-independent transcriptional role: CFIm25 loss in human embryonic stem cells altered RNA Pol II occupancy at gene bodies without significantly changing global APA, suggesting NUDT21 influences transcription directly.

    Evidence CRISPR/Cas9 CFIm25 knockout in hESCs, RNA Pol II ChIP-seq, APA profiling

    PMID:35491945

    Open questions at the time
    • Mechanism linking CFIm25 to Pol II occupancy not defined
    • Whether this APA-independent role operates broadly or is stem cell-specific
  10. 2022 High

    Novel interaction partners and clinical contexts were identified: FXR1 forms a complex with CFIm25/CFIm68 for TRAF1 mRNA processing, and a CRISPR screen revealed that NUDT21 deletion increases CD19 surface expression in B-ALL, sensitizing cells to immunotherapy — with NUDT21 upregulation observed at clinical relapse.

    Evidence FXR1–CFIm co-IP and 3' processing assays (PMID:35194031); genome-wide CRISPR screen in B-ALL with CD19 isoform analysis and CAR-T sensitivity assays (PMID:36138187)

    PMID:35194031 PMID:36138187

    Open questions at the time
    • Whether FXR1–CFIm complex regulates APA broadly or only specific targets
    • Clinical utility of NUDT21 modulation for immunotherapy resistance not tested in patients
  11. 2023 Medium

    Post-translational regulation of NUDT21 stability was delineated, and biomolecular condensate biology emerged: TRIP12 E3 ligase promotes NUDT21 proteasomal degradation (recruited by LINC00921); PABPN1 aggregates sequester CFIm25 impairing APA; and NUDT21/CPSF6 form liquid-like condensates upon HIV-1 nuclear entry that are required for productive infection.

    Evidence TRIP12–NUDT21 co-IP and ubiquitination assays (PMID:37999979); PABPN1 phase transition and CFIm25 sequestration assays (PMID:37422193); immunofluorescence of NUDT21/CPSF6 condensates with hexanediol and capsid mutant infection assays (PMID:37414787)

    PMID:37414787 PMID:37422193 PMID:37999979

    Open questions at the time
    • Whether TRIP12 and TRIM65 target NUDT21 in the same or different contexts
    • Functional consequence of PABPN1-mediated CFIm25 sequestration on global APA not profiled
    • Whether NUDT21–CPSF6 condensates serve roles beyond HIV-1 infection
  12. 2024 High

    The ubiquitination and methylation codes controlling NUDT21 were mapped: TRIM65 catalyzes K48-linked polyubiquitination at NUDT21 K56 for proteasomal degradation and consequent 3' UTR shortening of fibrotic genes, while PRMT7-mediated mono-methylation shifts APA to suppress oncogenicity, with HDAC2 acting as eraser and miR-181a/b identified as upstream suppressors of NUDT21 mRNA in fibrotic contexts.

    Evidence Yeast two-hybrid, co-IP, K56 ubiquitination site mapping, and in vivo AAV knockdown (PMID:38951701); PRMT7 methylation assays with transgenic mouse (PMID:39208673); miR-181a/b targeting validated by luciferase reporter and bleomycin mouse model (PMID:39250282)

    PMID:38951701 PMID:39208673 PMID:39250282

    Open questions at the time
    • Cross-talk between ubiquitination (K56) and methylation/lactylation (K23) not investigated
    • Cell-type specificity of TRIM65 vs. TRIP12 E3 ligase activity on NUDT21 unclear
  13. 2025 Medium

    Lactylation was identified as a novel activating PTM: AARS1-catalyzed lactylation at K23 (erased by HDAC2) enhances NUDT21–CPSF6 interaction and CFIm complex function, lengthening the FDX1 3' UTR and conferring cuproptosis resistance; concurrently, NUDT21 was shown to localize at active promoters and interact with transcription factors MYB, RUNX1, and GATA3 to drive MYC transcription in T-ALL, and IGF2BP3 was found to recruit NUDT21 to m6A-modified sites for APA of SPTBN1.

    Evidence Lactylation mass spectrometry with writer/eraser mapping, co-IP, APA profiling, and xenograft model (PMID:40425546); ChIP-seq of NUDT21 at promoters with TF co-IPs in T-ALL (PMID:41926643); IGF2BP3–NUDT21 co-IP with m6A-dependent APA of SPTBN1 (PMID:40301554)

    PMID:40301554 PMID:40425546 PMID:41926643

    Open questions at the time
    • Whether lactylation-enhanced CFIm assembly is a general metabolic sensor or context-specific
    • Structural basis for how PTMs at K23 alter CPSF6 binding affinity unknown
    • Whether NUDT21's promoter-proximal transcription factor interactions require its RNA-binding activity
  14. 2026 High

    Dose-dependent NUDT21 functions were resolved: moderate suppression causes maturation arrest in stem cells via APA-driven loss of miRNA regulation of differentiation genes, while complete loss additionally disrupts co-translational assembly of nuclear pore complexes through 3' UTR shortening of nucleoporin mRNAs, and NUDT21 itself is regulated by APA of its own 3' UTR during macrophage differentiation (PCBP1 binding controls translation).

    Evidence Graded knockdown in multiple stem cell types with 3' UTR deletion knockin models and NPC assembly assays (PMID:41580420); PCBP1–NUDT21 3'UTR RIP and ribosome association analysis during macrophage differentiation (PMID:41830116)

    PMID:41580420 PMID:41830116

    Open questions at the time
    • Whether NPC assembly defects are the primary cause of proteotoxic stress or a secondary effect
    • Threshold of NUDT21 protein required for normal NPC biogenesis not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive structural model of the full CFIm heterotetramer bound to a pre-mRNA substrate with mapped PTM sites is lacking, and the mechanistic rules determining how NUDT21 chooses between APA regulation and APA-independent transcriptional roles at specific genomic loci remain undefined.
  • No full-length CFIm complex structure with pre-mRNA substrate
  • Decision mechanism between APA-dependent and APA-independent gene regulation unknown
  • Interplay among ubiquitination, methylation, and lactylation at different NUDT21 residues not systematically studied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 8 GO:0003723 RNA binding 6 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
AARS1CPSF6FXR1HDAC2IGF2BP3IPS-1TRIM65TRIP12
Complex memberships
CFIm (Cleavage Factor Im)FXR1–CFIm complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 CFIm25 (NUDT21) forms a homodimer with a Nudix fold and binds UGUA RNA sequences in a sequence-specific manner; crystal structures reveal an intramolecular G:A Watson-Crick/sugar-edge base interaction in the UGUA element drives binding specificity, and mutational data support simultaneous recognition of two UGUA elements. CFIm25 has no detectable hydrolase activity despite its Nudix fold. Binding of RNA and the signaling molecule Ap4A to CFIm25 is mutually exclusive, suggesting small-molecule regulation of mRNA 3' processing. Crystal structures of CFIm25 homodimer in complex with UGUAAA and UUGUAU RNA; active-site mutagenesis; in vitro binding assays Proceedings of the National Academy of Sciences of the United States of America High 20479262
2014 CFIm25 (NUDT21) functions as a broad repressor of proximal poly(A) site usage genome-wide; its depletion causes 3' UTR shortening of at least 1,450 genes (11% of expressed mRNAs), increases expression of oncogenes including cyclin D1, and enhances cell proliferation and tumorigenic properties in glioblastoma cells. shRNA knockdown, RNA-seq with regression-model APA analysis, overexpression studies, in vivo tumour growth assays Nature High 24814343
2015 NUDT21 regulates alternative polyadenylation of the MECP2 3' UTR: elevated NUDT21 increases usage of the distal polyadenylation site, producing longer, inefficiently translated MECP2 mRNA isoforms and reducing MeCP2 protein levels; siRNA-mediated knockdown of NUDT21 in patient-derived duplication lymphoblasts restored MeCP2 to normal levels. Patient-derived lymphoblastoid cells (deletion and duplication CNV cases), siRNA knockdown, MECP2 mRNA isoform quantification, protein western blot eLife High 26312503
2017 Nudt21 directs differential alternative polyadenylation of over 1,500 transcripts during cell fate transitions, with APA-regulated proteins strongly enriched for chromatin regulators; suppression of these chromatin regulators neutralized the effect of Nudt21 knockdown during reprogramming, establishing a direct link between APA and chromatin signaling in cell fate control. shRNA screen in reprogramming assay, APA profiling, proteomics, epistasis by individual chromatin regulator knockdown Cell High 29249356
2016 Depletion of CFIm25 causes a shift to proximal poly(A) site usage within the glutaminase KGA 3' UTR and alters splicing to favor exclusion of the GAC 3' UTR; the shortened KGA 3' UTR remains partially subject to miR-23 repression but additional repression elements in the full-length UTR exist, demonstrating interplay between APA and miRNA-mediated regulation of glutamine metabolism. CFIm25 siRNA depletion, 3' RACE, isoform-specific RT-PCR, luciferase reporter assays, apoptosis assays RNA High 27095025
2017 NUDT21 co-localizes with AGO2 in P/GW bodies in normal liver cells; this co-localization is diminished in HCC cancer cells. NUDT21 elongates the 3' UTR of mRNAs and enhances efficiency of AGO2-mRNA binding, thereby enhancing miRNA-mediated gene silencing. Co-localization by immunofluorescence, co-immunoprecipitation (NUDT21 as AGO2 interaction partner), 3' UTR reporter assays Cancer letters Medium 28964783
2019 NUDT21 promotes circRNA cyclization; UGUA sequences in pre-mRNAs are critical for circRNA formation. Knockdown of NUDT21 reduces circRNA levels, disrupting the circRNA-miRNA-mRNA ceRNA pathway in hepatocellular carcinoma. NUDT21 knockdown/overexpression, circRNA quantification by divergent PCR, UGUA motif mutagenesis in circRNA reporters Oncogene Medium 31570791
2018 NUDT21 knockdown increases proximal polyadenylation site usage in PSMB2 and CXXC5 3' UTRs, resulting in marked increases in PSMB2 and CXXC5 protein expression; knockdown of PSMB2 or CXXC5 suppresses HCC proliferation and invasion, placing these genes downstream of NUDT21-mediated APA. Global APA site profiling (3' READS), NUDT21 knockdown/overexpression, western blot, downstream gene knockdown epistasis Oncogene Medium 29780166
2020 Partial loss of Nudt21 (Nudt21+/- mice with ~30% protein reduction) causes learning deficits, cortical hyperexcitability, and misregulated APA in hippocampus. Partial inhibition of NUDT21 in human stem cell-derived neurons induces APA and protein-level misregulation of hundreds of genes, including intellectual disability genes. Nudt21+/- mouse model (haploinsufficiency), behavioral testing, cortical EEG, PAC-seq APA profiling, human iPSC-derived neurons with siRNA knockdown eLife High 32319885
2020 CFIm25 is downregulated in systemic sclerosis skin and fibroblasts; its depletion in normal skin fibroblasts causes 3' UTR shortening of key TGFβ-regulated fibrotic genes (including Col1a1, Fn-1) and increases their protein expression. Fibroblast-specific CFIm25 knockout mice show exaggerated bleomycin-induced skin fibrosis, and CFIm25 restoration attenuates fibrosis. shRNA knockdown, conditional fibroblast-specific knockout mice, bleomycin fibrosis model, APA profiling, protein western blot The Journal of experimental medicine High 31757866
2020 NUDT21 physically associates with IPS-1 (mitochondrial antiviral signaling protein) and mediates IPS-1 localization to stress granules (SGs) in response to poly(I:C) (viral dsRNA mimic). A fraction of NUDT21 localizes to mitochondria at rest and translocates to SGs upon viral stimulation. NUDT21 is required for efficient type I IFN induction in response to viral infection. Co-immunoprecipitation of NUDT21 and IPS-1, immunofluorescence localization, subcellular fractionation, poly(I:C) transfection, viral infection assays in HeLa and RAW264.7 cells, NUDT21 siRNA knockdown Journal of immunology Medium 33219146
2022 FXR1 interacts with CFIm25 (NUDT21) and CFIm68, forming a novel 3' processing complex that functions in sequence-specific poly(A) site recognition; this complex regulates 3' processing and nuclear stabilization of TRAF1 mRNA. Co-immunoprecipitation of FXR1 with CFIm25 and CFIm68, 3' end processing assays, TRAF1 mRNA stability assays Cell death & disease Medium 35194031
2022 NUDT21 limits CD19 mRNA polyadenylation and stability in B-ALL; NUDT21 deletion increases CD19 surface expression and sensitizes B-ALL cells to CD19-specific CAR-T and blinatumomab. Upregulation of NUDT21 mRNA coincides with CD19 loss at clinical relapse after immunotherapy. Genome-wide CRISPR-Cas9 screen, NUDT21 knockout in B-ALL cells, CD19 mRNA isoform analysis, CAR-T and blinatumomab sensitivity assays, patient sample analysis Nature immunology High 36138187
2023 PABPN1 aggregates (expanded alanine variants) sequester CFIm25 in an mRNA-dependent manner, consequently impairing CFIm25's function in alternative polyadenylation; poly(A) nucleotide is essential for PABPN1 condensation and aggregate formation in nuclear speckles. Biochemical phase transition assays, co-localization immunofluorescence, CFIm25 sequestration assays with expanded-polyalanine PABPN1, APA functional assays The Journal of biological chemistry Medium 37422193
2023 CPSF5 (NUDT21) co-localizes with CPSF6 in biomolecular condensates that form upon HIV-1 nuclear entry; these condensates are sensitive to osmotic stress and 1,6-hexanediol (consistent with liquid-like condensates). Preventing CPSF6/CPSF5 condensate formation inhibits wild-type HIV-1 infection but not capsid mutants that do not form condensates. Immunofluorescence localization in T cells and primary macrophages upon HIV-1 infection, condensate disassembly by hexanediol/osmotic stress, viral infection assays with capsid mutants Scientific reports Medium 37414787
2023 LINC00921 lncRNA controls NUDT21 protein stability by facilitating binding of NUDT21 to the E3 ubiquitin ligase TRIP12, promoting NUDT21 proteasomal degradation; LINC00921-induced NUDT21 destabilization leads to 3' UTR shortening of MED23 mRNA via APA, elevating MED23 protein and activating β-catenin/TCF/LEF oncogenes. Co-IP of NUDT21 with TRIP12, ubiquitination assays, NUDT21 protein stability assays, APA profiling (PAC-seq), MED23 3'UTR reporter Cell reports Medium 37999979
2023 NUDT21 knockdown in glioma cells causes 3' UTR shortening of LAMC1, removing miR-124/506 binding sites, thereby de-repressing LAMC1 protein expression; co-depletion of LAMC1 with NUDT21 abolished the NUDT21-knockdown-induced increase in glioma cell migration, establishing LAMC1 as a key APA effector of NUDT21 in glioma. PAC-seq APA profiling, qRT-PCR, western blot, miRNA target site analysis, LAMC1 co-depletion epistasis, migration assays Journal of neuro-oncology Medium 37389756
2024 TRIM65 E3 ubiquitin ligase interacts with NUDT21 and induces K48-linked polyubiquitination at lysine 56 of NUDT21, leading to its proteasomal degradation; TRIM65-mediated NUDT21 degradation alters 3'UTR-APA of pro-fibrotic genes (Col1a1, Fn-1, Tgfbr1, Wnt5a, Fzd2) and inhibits TGF-β1-mediated SMAD and ERK1/2 signaling. Yeast two-hybrid screen (TRIM65-NUDT21 interaction), co-IP, K48-linked ubiquitination assays, proteasome inhibitor rescue, APA profiling, conditional AAV knockdown in vivo Cell death and differentiation High 38951701
2024 PRMT7-mediated mono-methylation of NUDT21 induces a shift in 3'UTR usage, reducing oncogenicity; un-methylated NUDT21 promotes cancer growth and cuproptosis insensitivity in enzalutamide-resistant cells. HDAC2 acts as the enzymatic eraser of NUDT21 K23 mono-methylation. AARS1 is identified as the lactylation writer for NUDT21 (in a separate study). PRMT7 methylation assay, mono-methylation monoclonal antibody, conditional knockin transgenic mouse, APA profiling, metabolomics Drug resistance updates Medium 39208673
2025 L-lactate-induced lactylation of NUDT21 at K23 (catalyzed by AARS1, erased by HDAC2) enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3' UTR lengthening of FDX1 mRNA, attenuating FDX1 protein output and conferring cuproptosis resistance in esophageal squamous cell carcinoma. Lactylation mass spectrometry, co-IP of NUDT21 with CPSF6, AARS1 and HDAC2 writer/eraser assays, APA profiling, FDX1 3'UTR reporter, cuproptosis assays, mouse xenograft model Cell discovery High 40425546
2025 IGF2BP3 interacts with NUDT21 and recruits it to m6A-modified sites in intron 32 of SPTBN1 pre-mRNA, promoting usage of the proximal polyadenylation site and generating short SPTBN1 transcripts with oncogenic activity; the long SPTBN1 isoform inhibits tumor growth by binding CDK1 and blocking G2/M. Co-IP of IGF2BP3 with NUDT21, m6A site mapping, APA profiling, SPTBN1 isoform-specific functional assays, CDK1 binding assay Communications biology Medium 40301554
2025 NUDT21 interacts with CPSF6 to form the CFIm complex, regulating poly(A) site selection. Mycobacterium tuberculosis infection disrupts the NUDT21-CPSF6 interaction, impairing NUDT21's ability to bind UGUA motifs in the FTH1 3'UTR and altering APA of FTH1 to favor longer isoforms with enhanced protein synthesis. Co-IP of NUDT21 with CPSF6 in infected vs. uninfected macrophages, UGUA RNA binding assays, APA isoform analysis, NUDT21 siRNA knockdown bacterial survival assays Frontiers in cellular and infection microbiology Medium 40384984
2025 CFIm25 overexpression promotes macrophage differentiation through APA-mediated 3'UTR shortening of NFKB1, TAB2, and TBL1XR1 mRNAs, increasing their protein levels and activating the NF-κB pathway; knockdown of TAB2 and TBL1XR1 in CFIm25-overexpressing cells attenuates NF-κB activation and macrophage differentiation markers. CFIm25 overexpression/depletion in monocytic cell lines, mRNA 3'-end sequencing, NF-κB pathway western blotting, NF-κB inhibition, epistasis by TAB2/TBL1XR1 knockdown Cell communication and signaling Medium 40022203
2026 During monocyte-to-macrophage differentiation, alternative polyadenylation generates a shorter CFIm25 (NUDT21) 3'UTR lacking PCBP1 binding sites; PCBP1 suppresses CFIm25 translation in monocytes by binding to its long 3'UTR, and loss of PCBP1 binding during differentiation allows enhanced ribosome recruitment and CFIm25 protein upregulation. RNA immunoprecipitation (PCBP1 binding to NUDT21 3'UTR), ribosome association analysis, PCBP1 knockdown, APA isoform quantification FEBS letters Medium 41830116
2026 Nudt21 regulates stem cell self-renewal and differentiation in a dose-dependent manner: moderate suppression causes maturation arrest via 3'UTR shortening of differentiation mRNAs that escape miRNA regulation; complete suppression additionally shortens 3'UTRs of mRNAs encoding nucleoporin subunits, destabilizing nuclear pore complexes, causing proteotoxic stress, DNA damage, and cell cycle arrest. Deletion of alternative 3'UTRs of individual nucleoporins recapitulates these defects. Graded Nudt21 knockdown in multiple stem cell types, APA profiling, nucleoporin complex assembly assays, co-translational assembly analysis, 3'UTR deletion knockin models Nature communications High 41580420
2024 TGFβ1 downregulates NUDT21 in skin fibroblasts through induction of miR-181a and miR-181b, which directly target NUDT21 mRNA; miR-181a/b inhibitors attenuate bleomycin-induced skin fibrosis in mice in association with preserved NUDT21 expression. TGFβ1 treatment of skin fibroblasts, miR-181a/b quantification, luciferase 3'UTR reporter for NUDT21 targeting, miRNA mimic/inhibitor studies, bleomycin fibrosis mouse model FASEB journal Medium 39250282
2021 CFIm25 promotes NUDT21/CPSF6 interaction but its loss in human embryonic stem cells affects RNA Pol II occupancy at gene bodies and alters expression of proliferation/differentiation transcripts without significantly impacting global APA, revealing an APA-independent role in controlling gene transcription. CRISPR/Cas9 CFIm25 knockdown/mutant hESC lines, APA profiling, RNA Pol II ChIP-seq, differentiation assays RNA biology Medium 35491945
2025 N-acetyltransferase 10 (NAT10) catalyzes ac4C modification that promotes CPSF5 (NUDT21) binding to MVC viral RNA in an ac4C-dependent manner; NP1 recruits CPSF5 to MVC RNAs, and ac4C modification at nt 3311 promotes specific binding of CPSF5 to the target region to ensure precise alternative viral RNA processing. acRIP-seq, RedaC:T-seq, in vitro RNA binding assays, NP1-CPSF5 co-IP, ac4C site mutagenesis Nucleic acids research Medium 40167508
2020 NUDT21 suppresses small cell lung cancer cell proliferation by modulating the splicing of GLS1; hypoxia-induced HIF-1α downregulates NUDT21, which alters the expression ratio of GLS1 isoforms GAC and KGA, linking hypoxic tumor environments to aberrant glutamine metabolism. shRNA knockdown, HIF-1α overexpression, GLS1 isoform RT-PCR, xenograft model Biochemical and biophysical research communications Low 32228887
2025 NUDT21 localizes to transcriptionally active promoters in T-ALL cells and interacts with lineage-specific transcription factors MYB, RUNX1, and GATA3 to facilitate MYC transcription; as a CFIm complex component, NUDT21 also promotes distal poly(A) site usage of UBE2D3, generating long 3'UTR isoforms with enhanced mRNA stability and protein expression, sustaining leukemia via MYC-dependent signaling. ChIP-seq (NUDT21 at promoters), co-IP with MYB/RUNX1/GATA3, multi-omics APA profiling, UBE2D3 3'UTR reporter, ouabain NUDT21 degradation assay Advanced science Medium 41926643

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 359 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 130 20479262
2017 Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. Cell 105 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 88 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 63 28964783
2019 NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation. Theranostics 51 31695759
2022 NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. Nature immunology 46 36138187
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 34 31757866
2020 Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation. eLife 30 32319885
2016 MicroRNA-181a promotes proliferation and inhibits apoptosis by suppressing CFIm25 in osteosarcoma. Molecular medicine reports 30 27633853
2021 Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation. Oncogene 28 33619322
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 25 35965101
2017 Silencing NUDT21 Attenuates the Mesenchymal Identity of Glioblastoma Cells via the NF-κB Pathway. Frontiers in molecular neuroscience 24 29311812
2023 Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. Scientific reports 22 37414787
2018 Knockdown of NUDT21 inhibits proliferation and promotes apoptosis of human K562 leukemia cells through ERK pathway. Cancer management and research 21 30349365
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 19 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
2025 NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance. Cell discovery 18 40425546
2020 CFIm25-regulated lncRNA acv3UTR promotes gastric tumorigenesis via miR-590-5p/YAP1 axis. Oncogene 17 32066878
2020 NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing. Biochemical and biophysical research communications 16 32228887
2023 Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis. JCI insight 15 37737260
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 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 14 39208673
2021 NUDT21 Promotes Tumor Growth and Metastasis Through Modulating SGPP2 in Human Gastric Cancer. Frontiers in oncology 14 34660260
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
2024 TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative polyadenylation. Cell death and differentiation 12 38951701
2017 Silencing the cleavage factor CFIm25 as a new strategy to control Entamoeba histolytica parasite. Journal of microbiology (Seoul, Korea) 12 28956353
2024 Nudt21-mediated alternative polyadenylation of MZT1 3'UTR contributes to pancreatic cancer progression. iScience 11 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 10 39267105
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
2018 Effect of CFIm25 knockout on RNA polymerase II transcription. BMC research notes 9 30547832
2023 Relationship between NUDT21 mediated alternative polyadenylation process and tumor. Frontiers in oncology 8 36816917
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
2024 NUDT21 regulates lysyl oxidase-like 2(LOXL2) to influence ECM protein cross-linking in silica-induced pulmonary fibrosis. Ecotoxicology and environmental safety 7 39700768
2023 NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. Journal of neuro-oncology 7 37389756
2019 The role of NUDT21 in microRNA-binging sites of EZH2 gene increases the of risk preeclampsia. Journal of cellular and molecular medicine 7 30883033
2023 Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression. Molecular oncology 6 37356089
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
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
2025 The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κB pathway. Cell communication and signaling : CCS 5 40022203
2025 IGF2BP3 recruits NUDT21 to regulate SPTBN1 alternative polyadenylation and drive ovarian cancer progression. Communications biology 5 40301554
2021 CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation. RNA biology 5 35491945
2020 CFIm25 in Solid Tumors: Current Research Progress. Technology in cancer research & treatment 5 32643564
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
2024 NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis. Journal of cancer research and clinical oncology 4 38195952
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
2020 [Effect of NUDT21 on Alternative Splicing of Transcripts in K562 Cells]. Zhongguo shi yan xue ye xue za zhi 2 33067945
2025 CFIm25-Dependent Alternative Polyadenylation in AKT2 mRNA Programs Macrophage Polarization. bioRxiv : the preprint server for biology 1 40667110
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
2025 Mycobacterium tuberculosis modulates NUDT21-mediated alternative polyadenylation to enhance FTH1 expression in macrophages and promotes intracellular growth. Frontiers in cellular and infection microbiology 0 40384984
2025 Alternative Polyadenylation Releases PCBP1-Mediated Suppression of CFIm25 During Macrophage Differentiation. bioRxiv : the preprint server for biology 0 40667065
2025 NUDT21-mediated Alternative Polyadenylation of CDK19 Reprograms Cholesterol Biosynthesis to Drive Colorectal Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41255211
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