NUDT21

Summary

NUDT21 (nudix hydrolase 21, HGNC:13870) is a protein-coding gene on chromosome 16q13, encoding Cleavage and polyadenylation specificity factor subunit 5 (O43809). Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3’-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The protein encoded by this gene is one subunit of a cleavage factor required for 3’ RNA cleavage and polyadenylation processing. The interaction of the protein with the RNA is one of the earliest steps in the assembly of the 3’ end processing complex and facilitates the recruitment of other processing factors. This gene encodes the 25kD subunit of the protein complex, which is composed of four polypeptides.

Source: NCBI Gene 11051 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 10 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_007006

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13870
Approved symbol	NUDT21
Name	nudix hydrolase 21
Location	16q13
Locus type	gene with protein product
Status	Approved
Aliases	CFIM25
Ensembl gene	ENSG00000167005
Ensembl biotype	protein_coding
OMIM	604978
Entrez	11051

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 4 retained_intron

ENST00000300291, ENST00000563362, ENST00000563860, ENST00000566340, ENST00000567110, ENST00000568822, ENST00000612596, ENST00000891181, ENST00000937744, ENST00000937745

RefSeq mRNA: 1 — MANE Select: NM_007006 NM_007006

CCDS: CCDS10760

Canonical transcript exons

ENST00000300291 — 7 exons

Exon	Start	End
ENSE00001108677	56434331	56434445
ENSE00001108678	56439657	56439746
ENSE00001108679	56429133	56432733
ENSE00001108681	56446626	56446689
ENSE00001108686	56434754	56434829
ENSE00001482691	56451087	56451332
ENSE00003474828	56447789	56447989

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 142.1156 / max 790.5380, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157479	124.7166	1827
157480	17.3991	1807

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.53	gold quality
ganglionic eminence	UBERON:0004023	97.46	gold quality
cortical plate	UBERON:0005343	97.13	gold quality
ventricular zone	UBERON:0003053	96.99	gold quality
pons	UBERON:0000988	96.94	gold quality
caput epididymis	UBERON:0004358	96.78	gold quality
left testis	UBERON:0004533	96.69	gold quality
germinal epithelium of ovary	UBERON:0001304	96.49	gold quality
superior vestibular nucleus	UBERON:0007227	96.40	gold quality
calcaneal tendon	UBERON:0003701	96.37	gold quality
right testis	UBERON:0004534	96.31	gold quality
adrenal tissue	UBERON:0018303	96.19	gold quality
testis	UBERON:0000473	96.07	gold quality
endometrium	UBERON:0001295	95.67	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.64	gold quality
substantia nigra pars compacta	UBERON:0001965	95.57	gold quality
corpus epididymis	UBERON:0004359	95.52	gold quality
cauda epididymis	UBERON:0004360	95.47	gold quality
oocyte	CL:0000023	95.46	gold quality
trigeminal ganglion	UBERON:0001675	95.29	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.17	gold quality
penis	UBERON:0000989	94.98	gold quality
subthalamic nucleus	UBERON:0001906	94.90	gold quality
embryo	UBERON:0000922	94.87	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.87	gold quality
postcentral gyrus	UBERON:0002581	94.80	gold quality
urethra	UBERON:0000057	94.76	gold quality
stromal cell of endometrium	CL:0002255	94.73	gold quality
monocyte	CL:0000576	94.68	gold quality
skin of hip	UBERON:0001554	94.68	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

187 targeting NUDT21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• region in the subunit of CF I(m) involved in RNA binding, protein-protein interactions, and subcellular localization (PMID:15169763)
• Evidence that CFIm25 regulates alternative poly(A) site selection of genes with tandem poly(A) signals in their 3’-UTRs. (PMID:17098938)
• Results from crystallographic and biochemical experiments suggest that CF I(m)25 makes use of its Nudix fold to bind but not hydrolyze ATP and diadenosine tetraphosphate. (PMID:18445629)
• The crystal structure of human CPSF5 was solved at 1.9 A resolution. (PMID:18767156)
• Crystallographic and biochemical experiments suggest that CF I(m)25 specifically recognizes UGUA RNA sequence and binds to two UGUA simultaneously (PMID:20479262)
• crystal structures of the CFI(m)25 homodimer in complex with UGUAAA and UUGUAU RNA sequences (PMID:20479262)
• Data provide evidence that CFIm exists as a heterotetramer of 25-kD, 59-kD and 68-kD subunits of CFIm: CFIm25, CFIm59 and CFIm68. (PMID:20695905)
• Crystal structure of CFIm25-CFIm68 RRM heterotetramer illustrated that CFIm25 homodimer is clamped by two CFIm68 monomers on each side of the dimer interface. (PMID:21295486)
• Structure of a CFI(m)25/CFI(m)68 RRM heterotetramer and biochemical data indicated that CFIm25 specifically recognized two UGUA elements, CFIm68 facilitates looping of the intervening RNA. CFIm-mediated RNA looping may regulate alternative polyadnylation. (PMID:21295486)
• The authors identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation. (PMID:26312503)
• it was demonstrated that the CFIm25 protein was also downregulated in osteosarcoma tissues, and inhibited the proliferation and promoted the apoptosis of the cells. Elucidating the roles of miR181a and CFIm25 in osteosarcoma not only assists in further understanding the pathogenesis and progression of this disease, but also offers novel targets for effective therapies. (PMID:27633853)
• RNA sequence preferences of unconventional RNA-binding proteins, Nudt21 and CNBP, has been described. (PMID:27956239)
• Loss of NUDT21 shortened the 3’-UTR of various oncogenes in hepatocellular carcinoma cells. The shorter 3’-UTR contained less miRNA binding sites, which enabled the oncogenes to evade miRNA regulation and become overexpressed in HCC, leading to unregulated cancer cell proliferation. (PMID:28964783)
• NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5. (PMID:29780166)
• Findings suggest that CFIm25 plays an important role in lung cancer cell proliferation through regulating the alternative polyadenylation (APA) of oncogenes. (PMID:29928883)
• Pak1 expression is regulated by Nudt21. (PMID:30705404)
• CFIm25 down-regulation is a novel mechanism to elevate pro-fibrotic gene expression in pulmonary fibrosis (PMID:30830875)
• The data indicate that the aberrant expression of NUDT21 contributes to Preeclampsia (PE) by targeting 3’-UTR of EZH2 mRNA. These findings may provide novel targets for future investigations into therapeutic strategies for PE (PMID:30883033)
• NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. (PMID:31570791)
• NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation. (PMID:31695759)
• Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation. (PMID:31757866)
• NUDT21 suppresses the growth of small cell lung cancer by modulating GLS1 splicing. (PMID:32228887)
• Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation. (PMID:32319885)
• Involved microRNAs in alternative polyadenylation intervene in breast cancer via regulation of cleavage factor ““CFIm25"”. (PMID:32665581)
• NUDT21 knockdown inhibits proliferation and promotes apoptosis of pancreatic ductal adenocarcinoma through EIF2 signaling. (PMID:32707135)
• [Effect of NUDT21 on Alternative Splicing of Transcripts in K562 Cells]. (PMID:33067945)
• NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense. (PMID:33219146)
• Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation. (PMID:33619322)
• [Over-expression of NUDT21 inhibits the proliferation of HCT-116 colon cancer cells via blocking P53/CDK2/Rb pathway]. (PMID:35732608)
• The emerging roles of CFIm25 (NUDT21/CPSF5) in human biology and disease. (PMID:35965101)
• NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. (PMID:36138187)
• NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. (PMID:37389756)
• Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. (PMID:37414787)
• PABPN1 aggregation is driven by Ala expansion and poly(A)-RNA binding, leading to CFIm25 sequestration that impairs alternative polyadenylation. (PMID:37422193)
• A new pathway for the transformation of AML in MDS: APA mechanism regulated by NUDT21 and RUNX1. (PMID:37498064)
• Alternative polyadenylation reprogramming of MORC2 induced by NUDT21 loss promotes KIRC carcinogenesis. (PMID:37737260)
• LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation. (PMID:37999979)
• NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis. (PMID:38195952)
• Predictive Value of CFIm25 Expression in Peripheral Blood Monocytes for Coronary Atherosclerosis. (PMID:38322593)
• Pan-cancer analysis of NUDT21 and its effect on the proliferation of human head and neck squamous cell carcinoma. (PMID:38349866)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nudt21	ENSDARG00000003153
mus_musculus	Nudt21	ENSMUSG00000031754
rattus_norvegicus	Nudt21	ENSRNOG00000042983
drosophila_melanogaster	Cpsf5	FBGN0288470
caenorhabditis_elegans	cfim-1	WBGENE00009668

Protein

Protein identifiers

Cleavage and polyadenylation specificity factor subunit 5 — O43809 (reviewed: O43809)

Alternative names: Cleavage and polyadenylation specificity factor 25 kDa subunit, Cleavage factor Im complex 25 kDa subunit, Nucleoside diphosphate-linked moiety X motif 21, Nudix hydrolase 21, Pre-mRNA cleavage factor Im 68 kDa subunit

All UniProt accessions (3): O43809, H3BND3, H3BV41

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3’-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3’-end, so called cleavage and polyadenylation signals (pA signals). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3’-end formation. The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5’-UGUA-3’ elements localized in the 3’-untranslated region (UTR) for a huge number of pre-mRNAs. NUDT21/CPSF5 activates indirectly the mRNA 3’-processing machinery by recruiting CPSF6 and/or CPSF7. Binds to 5’-UGUA-3’ elements localized upstream of pA signals that act as enhancers of pre-mRNA 3’-end processing. The homodimer mediates simultaneous sequence-specific recognition of two 5’-UGUA-3’ elements within the pre-mRNA. Plays a role in somatic cell fate transitions and pluripotency by regulating widespread changes in gene expression through an APA-dependent function. Binds to chromatin. Binds to, but does not hydrolyze mono- and di-adenosine nucleotides.

Subunit / interactions. Homodimer (via N- and C-terminus); binds RNA as homodimer. Component of the cleavage factor Im (CFIm) complex which is a heterotetramer composed of two subunits of NUDT21/CPSF5 and two subunits of CPSF6 or CPSF7 or a heterodimer of CPSF6 and CPSF7. The cleavage factor Im (CFIm) complex associates with the CPSF and CSTF complexes to promote the assembly of the core mRNA 3’-processing machinery. Interacts with CPSF6 (via the RRM domain); this interaction is direct and enhances binding to RNA. Interacts with CPSF7 (PubMed:29276085, Ref.30). Interacts with FIP1L1; this interaction occurs in a RNA sequence-specific manner. Interacts with PABPN1. Interacts (via N-terminus) with PAPOLA (via C-terminus); this interaction is direct and diminished by acetylation. Interacts with SNRNP70. Interacts with VIRMA.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in the heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Acetylated mainly by p300/CBP, recruited to the complex by CPSF6. Acetylation decreases interaction with PAPAO. Deacetylated by the class I/II HDACs, HDAC1, HDAC3 and HDAC10, and by the class III HDACs, SIRT1 and SIRT2.

Similarity. Belongs to the Nudix hydrolase family. CPSF5 subfamily.

RefSeq proteins (1): NP_008937* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000086	NUDIX_hydrolase_dom	Domain
IPR015797	NUDIX_hydrolase-like_dom_sf	Homologous_superfamily
IPR016706	Cleav_polyA_spec_factor_su5	Family

Pfam: PF13869

UniProt features (51 total): strand 15, mutagenesis site 11, modified residue 6, helix 6, sequence conflict 3, region of interest 3, site 2, initiator methionine 1, chain 1, domain 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
5R4Q	X-RAY DIFFRACTION	1.49
5R4R	X-RAY DIFFRACTION	1.5
5R67	X-RAY DIFFRACTION	1.52
5R4S	X-RAY DIFFRACTION	1.61
5R4T	X-RAY DIFFRACTION	1.68
5R4P	X-RAY DIFFRACTION	1.78
3BHO	X-RAY DIFFRACTION	1.8
5R64	X-RAY DIFFRACTION	1.84
3BAP	X-RAY DIFFRACTION	1.85
2CL3	X-RAY DIFFRACTION	1.9
3N9U	X-RAY DIFFRACTION	1.92
5R4U	X-RAY DIFFRACTION	1.92
5R66	X-RAY DIFFRACTION	2.02
3MDI	X-RAY DIFFRACTION	2.07
3MDG	X-RAY DIFFRACTION	2.22
5R65	X-RAY DIFFRACTION	2.28
2J8Q	X-RAY DIFFRACTION	2.3
3P5T	X-RAY DIFFRACTION	2.7
3P6Y	X-RAY DIFFRACTION	2.9
3Q2S	X-RAY DIFFRACTION	2.9
3Q2T	X-RAY DIFFRACTION	3.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43809-F1	90.63	0.79

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 55 (interaction with rna); 63 (interaction with rna)

Post-translational modifications (6): 15, 23, 29, 40, 56, 2

Mutagenesis-validated functional residues (11):

Position	Phenotype
23	abolishes acetylation.
29	no effect on acetylation.
55	reduces affinity for ugua rna by 88%.
63	reduces affinity for ugua rna by 99%.
81	reduces affinity for ugua rna by 12%.
103	reduces affinity for ugua rna by 99%.
103	reduces affinity for ugua rna by over 90%.
154	reduces affinity for ugua rna by 50%.
158	abolishes interaction with cpsf6; when associated with a-160.
160	abolishes interaction with cpsf6; when associated with a-158.
218	reduces interactions with cpsf6 and cpsf7 and decreases mrna 3’-processing activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-72187	mRNA 3’-end processing
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-77595	Processing of Intronless Pre-mRNAs
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA

MSigDB gene sets: 212 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, XU_GH1_AUTOCRINE_TARGETS_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_PROTEIN_HETEROTETRAMERIZATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, REACTOME_MRNA_3_END_PROCESSING

GO Biological Process (10): mRNA processing (GO:0006397), post-transcriptional regulation of gene expression (GO:0010608), cell differentiation (GO:0030154), mRNA 3’-end processing (GO:0031124), protein tetramerization (GO:0051262), protein heterotetramerization (GO:0051290), mRNA alternative polyadenylation (GO:0110104), co-transcriptional mRNA 3’-end processing, cleavage and polyadenylation pathway (GO:0180010), positive regulation of stem cell differentiation (GO:2000738), positive regulation of pro-B cell differentiation (GO:2000975)

GO Molecular Function (8): chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA binding (GO:0003729), mRNA 3’-UTR AU-rich region binding (GO:0035925), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), histone deacetylase binding (GO:0042826), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), mRNA cleavage and polyadenylation specificity factor complex (GO:0005847), mRNA cleavage factor complex (GO:0005849), nuclear body (GO:0016604), centriolar satellite (GO:0034451), paraspeckles (GO:0042382)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Processing of Capped Intron-Containing Pre-mRNA	1
RNA Polymerase II Transcription	1
Processing of Capped Intronless Pre-mRNA	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mRNA 3’-end processing	2
binding	2
RNA processing	1
mRNA metabolic process	1
regulation of gene expression	1
cellular developmental process	1
mRNA processing	1
RNA 3’-end processing	1
protein complex oligomerization	1
protein tetramerization	1
protein heterooligomerization	1
co-transcriptional RNA 3’-end processing, cleavage and polyadenylation pathway	1
positive regulation of cell differentiation	1
stem cell differentiation	1
regulation of stem cell differentiation	1
pro-B cell differentiation	1
positive regulation of lymphoid progenitor cell differentiation	1
regulation of pro-B cell differentiation	1
nucleic acid binding	1
RNA binding	1
mRNA 3’-UTR binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
enzyme binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
mRNA cleavage factor complex	1
nuclear protein-containing complex	1
nucleoplasm	1
intracellular membraneless organelle	1
centrosome	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

2820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUDT21	CPSF6	Q16630	999
NUDT21	CPSF7	Q8N684	998
NUDT21	VIRMA	Q69YN4	959
NUDT21	CPSF1	Q10570	859
NUDT21	CPSF2	Q9P2I0	824
NUDT21	CPSF3	Q9UKF6	820
NUDT21	CSTF2	P33240	807
NUDT21	CPSF4	O95639	787
NUDT21	CSTF1	Q05048	776
NUDT21	PCF11	O94913	774
NUDT21	PABPN1	Q86U42	770
NUDT21	CSTF3	Q12996	760
NUDT21	WDR33	Q9C0J8	717
NUDT21	SYMPK	Q92797	710
NUDT21	FIP1L1	Q6UN15	701

IntAct

271 interactions, top by confidence:

A	B	Type	Score
CPSF6	NUDT21	psi-mi:“MI:0407”(direct interaction)	0.890
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
NUDT21	NUDT21	psi-mi:“MI:0915”(physical association)	0.810
NUDT21	NUDT21	psi-mi:“MI:0407”(direct interaction)	0.810
NUDT21	CPSF7	psi-mi:“MI:0915”(physical association)	0.740
CPSF7	NUDT21	psi-mi:“MI:0915”(physical association)	0.740
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.740
NUDT21	MYL6	psi-mi:“MI:0915”(physical association)	0.740
NUDT21	CPSF6	psi-mi:“MI:0915”(physical association)	0.740
TRIM27	NUDT21	psi-mi:“MI:0915”(physical association)	0.720
NUDT21	TRIM27	psi-mi:“MI:0915”(physical association)	0.720
NUDT21	ATXN1	psi-mi:“MI:0915”(physical association)	0.700
NUDT21	CPSF6	psi-mi:“MI:0407”(direct interaction)	0.650
GOLGA2	NUDT21	psi-mi:“MI:0915”(physical association)	0.560
NUDT21	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (5599): NUDT21 (Affinity Capture-MS), NUDT21 (Affinity Capture-MS), NUDT21 (Two-hybrid), NUDT21 (Two-hybrid), NUDT21 (Two-hybrid), CPSF7 (Two-hybrid), NUDT21 (Affinity Capture-MS), NUDT21 (Affinity Capture-MS), NUDT21 (Affinity Capture-MS), NUDT21 (Affinity Capture-MS), NUDT21 (Affinity Capture-MS), NUDT21 (Reconstituted Complex), NUDT21 (Two-hybrid), NIF3L1 (Two-hybrid), CPSF7 (Two-hybrid)

ESM2 similar proteins: A5D796, B1AY13, D6WMX4, G5EF51, O15327, O43314, O43809, P0C0R5, P29993, P50851, P60670, P81128, Q01H84, Q21029, Q3V3E1, Q3ZCA2, Q4KM65, Q55E68, Q5R9I3, Q5RA60, Q5RAI8, Q5REW0, Q5ZLG9, Q6DCF6, Q6DIR8, Q6DJE4, Q6PJI9, Q6ZQB6, Q7L5Y6, Q7T3C6, Q80TR8, Q86VS3, Q8GXS3, Q8NFP9, Q8TAT6, Q8TF42, Q8VD65, Q8VDY4, Q8WSR4, Q91YM2

Diamond homologs: O43809, Q3ZCA2, Q4KM65, Q55E68, Q5RAI8, Q6DJE4, Q7T3C6, Q8GXS3, Q94AF0, Q9CQF3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NUDT21	“form complex”	“CFI complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	7	14.1×	4e-04
RNA Polymerase II Transcription Termination	6	13.4×	2e-03
RHOQ GTPase cycle	6	11.1×	3e-03
Processing of Capped Intron-Containing Pre-mRNA	8	6.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	5	12.6×	7e-03
negative regulation of translation	6	9.3×	7e-03
mRNA splicing, via spliceosome	8	5.8×	1e-02
mRNA processing	9	5.6×	7e-03
RNA splicing	8	5.6×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

10 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1027 predictions. Top by Δscore:

Variant	Effect	Δscore
16:56434325:CTGTA:C	donor_loss	1.0000
16:56434326:TGTAC:T	donor_loss	1.0000
16:56434327:GTACC:G	donor_loss	1.0000
16:56434328:TACCT:T	donor_loss	1.0000
16:56434329:A:T	donor_loss	1.0000
16:56434330:C:CA	donor_loss	1.0000
16:56434330:CCTG:C	donor_gain	1.0000
16:56434441:CAAGG:C	acceptor_gain	1.0000
16:56434443:AGG:A	acceptor_gain	1.0000
16:56434444:GG:G	acceptor_gain	1.0000
16:56434446:C:CC	acceptor_gain	1.0000
16:56434749:CTTA:C	donor_loss	1.0000
16:56434750:TTACC:T	donor_loss	1.0000
16:56434752:A:AC	donor_gain	1.0000
16:56434753:C:CC	donor_gain	1.0000
16:56434826:GATAC:G	acceptor_loss	1.0000
16:56434828:TA:T	acceptor_gain	1.0000
16:56434829:ACTGA:A	acceptor_loss	1.0000
16:56434830:C:CC	acceptor_gain	1.0000
16:56434830:CTGA:C	acceptor_loss	1.0000
16:56439652:CTGA:C	donor_loss	1.0000
16:56439653:TGACC:T	donor_loss	1.0000
16:56439654:GAC:G	donor_loss	1.0000
16:56439655:A:C	donor_loss	1.0000
16:56439656:C:CA	donor_loss	1.0000
16:56446690:C:CC	acceptor_gain	1.0000
16:56447784:CTT:C	donor_loss	1.0000
16:56447785:TTAC:T	donor_loss	1.0000
16:56447786:TACAG:T	donor_loss	1.0000
16:56447787:A:AC	donor_gain	1.0000

AlphaMissense

1481 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:56432730:G:C	F222L	1.000
16:56432730:G:T	F222L	1.000
16:56432732:A:G	F222L	1.000
16:56434331:C:A	R221M	1.000
16:56434346:G:C	P216R	1.000
16:56434346:G:T	P216H	1.000
16:56434349:A:G	L215P	1.000
16:56434349:A:T	L215H	1.000
16:56434351:A:C	S214R	1.000
16:56434351:A:T	S214R	1.000
16:56434353:T:G	S214R	1.000
16:56434355:G:A	S213F	1.000
16:56434355:G:T	S213Y	1.000
16:56434358:A:T	I212N	1.000
16:56434367:C:A	G209V	1.000
16:56434367:C:G	G209A	1.000
16:56434367:C:T	G209E	1.000
16:56434368:C:G	G209R	1.000
16:56434368:C:T	G209R	1.000
16:56434370:T:C	Y208C	1.000
16:56434371:A:C	Y208D	1.000
16:56434371:A:G	Y208H	1.000
16:56434373:C:T	G207E	1.000
16:56434381:A:C	N204K	1.000
16:56434381:A:T	N204K	1.000
16:56434385:T:A	D203V	1.000
16:56434386:C:G	D203H	1.000
16:56434391:A:C	L201W	1.000
16:56434391:A:G	L201S	1.000
16:56434394:T:A	E200V	1.000

dbSNP variants (sampled 300 via entrez): RS1000562495 (16:56441385 C>A,T), RS1000838469 (16:56432980 G>T), RS1001794402 (16:56442645 C>T), RS1002322328 (16:56447699 A>C), RS1002723474 (16:56432495 G>A,C,T), RS1002987236 (16:56450642 C>G), RS1003282236 (16:56438095 A>G), RS1003369513 (16:56443798 C>A), RS1003823991 (16:56428676 T>C), RS1003867850 (16:56440807 C>A,T), RS1003929780 (16:56433743 A>G), RS1004401022 (16:56434016 C>T), RS1004408471 (16:56441063 T>C,G), RS1004932290 (16:56432227 C>G,T), RS1004958930 (16:56439509 A>T)

Disease associations

OMIM: gene MIM:604978 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724780 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.83	Kd	1465	nM	CHEMBL5653589
5.83	ED50	1465	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148898: Binding affinity to human NUDT21 incubated for 45 mins by Kinobead based pull down assay	kd	1.4647	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression, decreases methylation	4
bisphenol A	affects expression, decreases expression	2
Acetaminophen	decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
sodium arsenite	increases activity	1
tetrabromobisphenol A	decreases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
hexabrominated diphenyl ether 153	increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Troglitazone	decreases expression	1
Arsenic	increases ubiquitination	1
Benzo(a)pyrene	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651940	Binding	Binding affinity to human NUDT21 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.