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Study on the mechanism of action of NUDT21 in acute T-lymphocytic leukemia [CUT&Tag]

ABSTRACT: Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that regulates transcript stability, localization, and translation. While dysregulated APA has been implicated in multiple cancers, its role in T-cell acute lymphoblastic leukemia (T-ALL) remains poorly understood. Here, we identify NUDT21, a core subunit of the APA machinery, as an essential oncogenic regulator in T-ALL. NUDT21 is significantly upregulated in T-ALL patient samples and associated with poor prognosis. Functional assays demonstrate that NUDT21 knockdown inhibits T-ALL cell proliferation, induces apoptosis, and suppresses leukemia progression in vivo. Integrative PAS-seq and RNA-seq analysis reveals that NUDT21 maintains distal polyadenylation site usage of oncogenic transcripts, including UBE2D3, whose 3′UTR shortening upon NUDT21 loss leads to decreased expression and impaired leukemic cell growth. In addition to its APA role, NUDT21 occupies gene regulatory regions and directly activates transcriptional programs enriched for MYC and E2F targets, promoting cell cycle progression and ribosome biogenesis. Pharmacological suppression of NUDT21 using ouabain, a cardiac glycoside, downregulates UBE2D3 and E2F/MYC effectors, resulting in robust anti-leukemic effects.Our findings reveal a dual regulatory role of NUDT21 in T-ALL, functioning through both APA-dependent and APA-independent mechanisms to sustain leukemic proliferation. Targeting NUDT21 or its downstream programs represents a promising therapeutic strategy for T-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305852 | GEO | 2026/02/01

REPOSITORIES: GEO

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Study on the mechanism of action of NUDT21 in acute T-lymphocytic leukemia [eCLIP-seq]

Project description:Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that regulates transcript stability, localization, and translation. While dysregulated APA has been implicated in multiple cancers, its role in T-cell acute lymphoblastic leukemia (T-ALL) remains poorly understood. Here, we identify NUDT21, a core subunit of the APA machinery, as an essential oncogenic regulator in T-ALL. NUDT21 is significantly upregulated in T-ALL patient samples and associated with poor prognosis. Functional assays demonstrate that NUDT21 knockdown inhibits T-ALL cell proliferation, induces apoptosis, and suppresses leukemia progression in vivo. Integrative PAS-seq and RNA-seq analysis reveals that NUDT21 maintains distal polyadenylation site usage of oncogenic transcripts, including UBE2D3, whose 3′UTR shortening upon NUDT21 loss leads to decreased expression and impaired leukemic cell growth. In addition to its APA role, NUDT21 occupies gene regulatory regions and directly activates transcriptional programs enriched for MYC and E2F targets, promoting cell cycle progression and ribosome biogenesis. Pharmacological suppression of NUDT21 using ouabain, a cardiac glycoside, downregulates UBE2D3 and E2F/MYC effectors, resulting in robust anti-leukemic effects.Our findings reveal a dual regulatory role of NUDT21 in T-ALL, functioning through both APA-dependent and APA-independent mechanisms to sustain leukemic proliferation. Targeting NUDT21 or its downstream programs represents a promising therapeutic strategy for T-ALL.

2026-02-01 | GSE305851 | GEO

Study on the mechanism of action of NUDT21 in acute T-lymphocytic leukemia [PAS-seq]

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Study on the mechanism of action of NUDT21 in acute T-lymphocytic leukemia [RNA-Seq]

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Nudt21 KO and Nudt21 Hypomorph esophageal basal cells

Project description:Most mammalian genes contain multiple polyadenylation signals, yielding mRNA-isoforms with different 3’UTR ends via alternative polyadenylation (APA). While APA can profoundly impact protein levels, its physiological roles remain elusive. Here, we show that the APA regulator Nudt21 is essential for tissue regeneration by maintaining proliferative stem and progenitor cells. Leveraging a Nudt21-titratable system, we show that APA modulation impacts stem/progenitor cell function in a dose-dependent manner. Intermediate levels elicit a differentiation arrest owing to the 3’UTR-shortening of chromatin-associated mRNAs that escape miRNA regulation. By contrast, complete Nudt21 loss disrupts stem cell self-renewal by shortening the 3’UTRs of mRNAs encoding for essential multiprotein complexes, including the nuclear pore, leading to their degradation. Critically, deletion of the alternative 3’UTR of Nucleoporin-160 recapitulates defects observed with Nudt21 loss. Our findings uncover a previously unrecognized dual role for APA in tissue maintenance, by modulating differentiation-associated gene expression and preserving multiprotein complexes essential for proliferation.

2025-11-21 | GSE280706 | GEO

NUDT21 Shapes Macrophage Transcriptomes through alternative polyadenylation in ARDS

Project description:Defining the molecular mechanisms governing macrophage-driven inflammation is essential for developing targeted interventions for ARDS. One such mechanism could be alternative polyadenylation (APA), a post-transcriptional regulatory process that plays a critical role in gene regulation. Most mammalian genes, including key proinflammatory mediators, contain multiple polyadenylation sites (PAS). APA regulates the addition of poly(A) tails at alternative PAS, generating transcripts with different 3' UTR lengths. One key regulator of APA is Nudix Hydrolase 21 (NUDT21), a critical cleavage factor Im (CFIm) component. However, whether NUDT21-mediated APA plays a role in inflammation during ARDS is not known. Thus, the goal of this study is to identify the APA genes regulated by NUDT21 in macrophages.

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NUDT21 Negatively Regulates PSMB2 and CXXC5 by Alternative Polyadenylation and Contributes to Hepatocellular Carcinoma Suppression

Project description:HCC is the third leading cause of cancer-related deaths worldwide. However, the molecular mechanisms underlying the progression of HCC is still largely elusive. NUDT21 (CFIm25) is an important mediator of 3′ UTR APA and demonstrates a causal relationship between alternative polyadenylation and cancer cell proliferation. Although the function of NUDT21 has been explored in glioblastoma tumor, the functional significance of NUDT21 in solid tumors is not well understood. In this study, we observed that NUDT21 is suppressed in human HCC tissues, compared to adjacent noncancerous tissues. In addition we found that the HCC patients with suppressed NUDT21 are statistically associated with poor outcomes. These observations suggest NUDT21 possibly functions as tumor suppressor in hepatocellular carcinoma (HCC).

2018-01-25 | E-MTAB-6368 | biostudies-arrayexpress

Nudt21 ablation in macrophages induces constitutive autophagy activation and diminishes inflammation in inflammatory diseases

Project description:Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) in regulating innate immunity remains unclear. In this study, we demonstrate that Nudt21, a crucial RNA-binding component of the APA machinery, is significantly upregulated in various inflammatory settings. Utilizing myeloid-specific Nudt21-deficient mice, we reveal a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes by mediating selective 3’UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display enhanced autophagic activity, which leads to reduced cytokine secretion.

2025-01-24 | GSE267291 | GEO

NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance

Project description:Alternative polyadenylation (APA) serves as a critical mechanism for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3′ untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3′ UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation “writer” catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic “eraser”. Clinically, elevated LDHA and NUDT21 levels correlate with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.

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Interacting proteins of NUDT21 identified by IP-MS

Project description:Alternative polyadenylation modulates gene expresion via changing the length of 3'UTR. Among the complexes involving in APA, CFIm complex plays a central role in determining the usage of proximal PAS versus distal one. NUDT21, also named as CFIm25 and CPSF5, is the core component of CFIm complex. To date, except CPSF6 and CPSF7, there are few proteins reported to interact with NUDT21. In this project, the interactome of NUDT21 was identified by IP-MS.

2022-01-21 | PXD031134 |

Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling

Project description:Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in restricting cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, polycomb, and trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are largely responsible for Nudt21’s effect on reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.

2018-01-08 | PXD008078 | Pride

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