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
• Regional missense constraint (gnomAD): 3 of 5 regions constrained (≈84% of expected missense variation)
• GTEx eGene: eQTL in 18 tissues, sQTL in 29 (q < 0.05)
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.95 (loss-of-function intolerant), LOEUF 0.51 (moderately constrained)
• MANE Select transcript: NM_007006
• Interaction hub: 2,007 STRING partners (top 7% of genes corpus-wide)

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: 15 — 10 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000300291

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 2, TSL 5: 1

ENST00000300291, ENST00000563362, ENST00000563860, ENST00000566340, ENST00000567110, ENST00000568822, ENST00000612596, ENST00000891181, ENST00000937744, ENST00000937745, ENST00001082866, ENST00001082871, ENST00001095500, ENST00001110253, ENST00001135210

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.

Highest expression (Bgee): primordial germ cell in gonad, ganglionic eminence, cortical plate, ventricular zone, pons.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NUDT21 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 29 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 47 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	1.7e-62	+0.78	16:56451339:G:T
Brain Caudate basal ganglia	sqtl	4.4e-54	+2.67	16:56363655:G:C
Brain Nucleus accumbens basal ganglia	sqtl	7.1e-45	+2.71	16:56363655:G:C
Brain Putamen basal ganglia	sqtl	7.6e-45	+2.75	16:56361585:T:C
Brain Cortex	sqtl	1.0e-42	+2.47	16:56361585:T:C
Brain Hypothalamus	sqtl	6.3e-39	+2.59	16:56431490:C:G
Brain Hippocampus	sqtl	2.6e-36	+2.58	16:56431490:C:G
Brain Spinal cord cervical c-1	sqtl	1.2e-27	+2.83	16:56363655:G:C
Brain Anterior cingulate cortex BA24	sqtl	1.7e-25	+2.46	16:56363655:G:C
Brain Substantia nigra	sqtl	6.6e-23	+2.72	16:56431490:C:G
Ovary	sqtl	1.0e-22	+2.91	16:56503905:C:A
Brain Amygdala	sqtl	2.9e-18	+2.71	16:56363655:G:C
Artery Tibial	sqtl	1.9e-10	-0.91	16:56528072:A:C
Brain Hypothalamus	eqtl	7.4e-09	+0.31	16:56445204:T:C
Esophagus Muscularis	sqtl	4.1e-08	-0.77	16:56466264:T:A
Thyroid	sqtl	1.3e-07	-0.68	16:56482302:G:C
Adipose Subcutaneous	eqtl	1.4e-06	+0.20	16:56451339:G:T
Colon Sigmoid	sqtl	5.7e-06	-0.79	16:56452995:T:TA
Adipose Visceral Omentum	sqtl	7.0e-05	-1.11	16:56357509:G:A
Esophagus Gastroesophageal Junction	sqtl	2.6e-04	-0.69	16:56459287:C:G

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 298 tissues 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
islet of Langerhans	UBERON:0000006	94.63	gold quality
epithelium of nasopharynx	UBERON:0001951	94.61	gold quality
nasopharynx	UBERON:0001728	94.59	gold quality
secondary oocyte	CL:0000655	94.51	gold quality
renal medulla	UBERON:0000362	94.46	gold quality
lateral globus pallidus	UBERON:0002476	94.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.39	gold quality
rectum	UBERON:0001052	94.38	gold quality
mononuclear cell	CL:0000842	94.36	gold quality
parietal lobe	UBERON:0001872	94.36	gold quality
tonsil	UBERON:0002372	94.23	gold quality
leukocyte	CL:0000738	94.22	gold quality
bone marrow	UBERON:0002371	94.17	gold quality
sperm	CL:0000019	94.08	gold quality
cartilage tissue	UBERON:0002418	94.05	gold quality
bone element	UBERON:0001474	94.04	gold quality
duodenum	UBERON:0002114	94.02	gold quality
ovary	UBERON:0000992	93.91	gold quality
tibia	UBERON:0000979	93.76	gold quality
colonic epithelium	UBERON:0000397	93.71	gold quality
trabecular bone tissue	UBERON:0002483	93.69	gold quality
oral cavity	UBERON:0000167	93.58	gold quality
pigmented layer of retina	UBERON:0001782	93.57	gold quality
left ovary	UBERON:0002119	93.57	gold quality
retina	UBERON:0000966	93.55	gold quality
lymph node	UBERON:0000029	93.51	gold quality
mammary duct	UBERON:0001765	93.51	gold quality
superficial temporal artery	UBERON:0001614	93.40	gold quality
caecum	UBERON:0001153	93.30	gold quality
adult organism	UBERON:0007023	93.30	gold quality
colonic mucosa	UBERON:0000317	93.27	gold quality
jejunum	UBERON:0002115	93.08	gold quality
jejunal mucosa	UBERON:0000399	93.05	gold quality
gall bladder	UBERON:0002110	92.99	gold quality
parietal pleura	UBERON:0002400	92.96	gold quality
pancreas	UBERON:0001264	92.94	gold quality
right ovary	UBERON:0002118	92.94	gold quality
tendon	UBERON:0000043	92.90	gold quality
vermiform appendix	UBERON:0001154	92.89	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.88	gold quality
uterus	UBERON:0000995	92.83	gold quality
superior frontal gyrus	UBERON:0002661	92.83	gold quality
upper leg skin	UBERON:0004262	92.83	gold quality
corpus callosum	UBERON:0002336	92.81	gold quality
eye	UBERON:0000970	92.71	gold quality
seminal vesicle	UBERON:0000998	92.71	gold quality
ventral tegmental area	UBERON:0002691	92.63	gold quality
male germ cell	CL:0000015	92.61	gold quality
female reproductive system	UBERON:0000474	92.59	gold quality
ectocervix	UBERON:0012249	92.50	gold quality
palpebral conjunctiva	UBERON:0001812	92.49	gold quality
body of pancreas	UBERON:0001150	92.45	gold quality
pericardium	UBERON:0002407	92.45	gold quality
bone marrow cell	CL:0002092	92.42	gold quality
nucleus accumbens	UBERON:0001882	92.40	gold quality
synovial joint	UBERON:0002217	92.38	gold quality
thoracic mammary gland	UBERON:0005200	92.35	gold quality
lower lobe of lung	UBERON:0008949	92.33	gold quality
mammary gland	UBERON:0001911	92.29	gold quality
esophagus mucosa	UBERON:0002469	92.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.28	gold quality
endocervix	UBERON:0000458	92.23	gold quality
mammalian vulva	UBERON:0000997	92.22	gold quality
adrenal gland	UBERON:0002369	92.21	gold quality
left adrenal gland	UBERON:0001234	92.20	gold quality
right adrenal gland	UBERON:0001233	92.19	gold quality
prefrontal cortex	UBERON:0000451	92.14	gold quality
right adrenal gland cortex	UBERON:0035827	92.12	gold quality
dorsal root ganglion	UBERON:0000044	92.11	gold quality
urinary bladder	UBERON:0001255	92.09	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	93.7	medium
Hippocampal formation	tissue	67.2
Testis	tissue	66.0	medium
Septum	tissue	65.1
Midbrain	tissue	63.7
Corpus callosum	tissue	63.7
Basal ganglia	tissue	63.1	medium
Putamen	tissue	62.9
Ventral forebrain	tissue	62.4
Pons	tissue	61.6
Entorhinal cortex	tissue	61.6
Tonsil	tissue	61.4	medium
Thalamus	tissue	61.2
Hypothalamus	tissue	61.2
Spinal cord	tissue	60.7
Locus coeruleus	tissue	60.6
Bone marrow	tissue	60.6	medium
Olfactory bulb	tissue	60.6
Substantia nigra	tissue	59.7
Cerebral cortex	tissue	59.6	medium
Motor cortex	tissue	59.6
Temporal cortex	tissue	59.5
Amygdala	tissue	59.3
Retrosplenial and cingulate cortex	tissue	59.2
Retrosplenial cortex	tissue	59.0
Periaqueductal gray	tissue	58.6
Prefrontal cortex	tissue	58.3
Medulla oblongata	tissue	58.3
Somatosensory cortex	tissue	58.3
Insular cortex	tissue	57.5
Occipital cortex	tissue	57.2
Nucleus accumbens	tissue	55.3
Superior colliculi	tissue	55.3
Thymus	tissue	54.4
Lymph node	tissue	52.8	medium
Ovary	tissue	49.4	not detected
Choroid plexus	tissue	48.4
Hippocampus	tissue	47.3	medium
Duodenum	tissue	46.4	medium
Postcentral gyrus	tissue	43.6
Kidney	tissue	39.2	high
Parathyroid gland	tissue	37.7	high
Esophagus	tissue	37.5	medium
Rectum	tissue	37.5	medium
Cervix	tissue	37.3	low
Urinary bladder	tissue	37.1	low
Breast	tissue	36.8	medium
Colon	tissue	36.7	medium
Endometrium 1	tissue	36.7	medium
Placenta	tissue	36.1	low
Appendix	tissue	35.6	low
Tongue	tissue	35.2
Thyroid gland	tissue	34.9	medium
Liver	tissue	34.5	medium
Fallopian tube	tissue	33.7	medium
Spleen	tissue	32.5	medium
Smooth muscle	tissue	32.3	medium
Small intestine	tissue	32.3	medium
Stomach 1	tissue	31.9	high
Pancreas	tissue	30.5	low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Arcuate nucleus (74.4), Dorsal hippocampus (67.2), Lateral hypothalamic area (65.0), Perirhinal gyrus (64.8), White matter (63.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting NUDT21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 187 miRNAs:

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

gnomAD constraint: pLI 0.95, LOEUF 0.514, missense Z 3.77 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000300291 splits into 5 regions with different missense tolerance; 3 are missense-constrained (≈84% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
16:56,432,715–56,434,782	13 / 59.7	0.22	yes (p 1.5e-09)
16:56,434,783–56,434,822	13 / 16.6	0.79	no
16:56,434,823–56,451,089	27 / 149.5	0.18	yes (p 1.2e-23)
16:56,451,090–56,451,151	20 / 26.3	0.76	no
16:56,451,152–56,451,202	3 / 23.9	0.13	yes (p 2.0e-05)
DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): EFO-21 (-2.956), T.T (-2.784), RERF-GC-1B (-2.767), C32 (-2.726), KMS-20 (-2.701), MHH-ES-1 (-2.677), THP-1 (-2.673), UACC-893 (-2.673), C8166 (-2.655), KARPAS-299 (-2.64), NCI-H2170 (-2.634), BxPC-3 (-2.626), HD-MY-Z (-2.616), SU.86.86 (-2.611), Malme-3M (-2.594).

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915469) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased acute inflammation	1
increased susceptibility to injury	1
pulmonary fibrosis	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1
increased collagen level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q3ZCA2	100.0%	Diamond
Pongo abelii	Q5RAI8	100.0%	Diamond
Xenopus laevis	Q6DJE4	98.7%	Diamond
Arabidopsis thaliana	Q8GXS3	59.0%	Diamond
Dictyostelium discoideum	Q55E68	58.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GNAO1-AS1	ncRNA	26077
AMFR	protein-coding	267
GNAO1	protein-coding	2775
GNAO1-DT	ncRNA	283856
OGFOD1	protein-coding	55239
BBS2	protein-coding	583
MT4	protein-coding	84560
MIR3935	ncRNA	100500891

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 (53 total): strand 15, mutagenesis site 11, helix 8, modified residue 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 by resolution:

PDB	Title	Method	Resolution (Å)
5R4Q	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.49
5R4R	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.5
5R67	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.52
5R4S	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.61
5R4T	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.68
5R4P	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.78
3BHO	Crystal Structure of the 25kDa Subunit of Human Cleavage factor Im with Ap4A	X-RAY DIFFRACTION	1.8
5R64	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.84
3BAP	Crystal Structure of the 25 kDa Subunit of Human Cleavage Factor Im	X-RAY DIFFRACTION	1.85
2CL3	Crystal structure of human Cleavage and Polyadenylation Specificity Factor 5 (CPSF5)	X-RAY DIFFRACTION	1.9
3N9U	Crystal Structure of the Complex between the 25 kDa Subunit and the 59 kDa Subunit (RRM …	X-RAY DIFFRACTION	1.92
5R4U	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	1.92
5R66	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	2.02
3MDI	Crystal Structure of the 25kDa Subunit of Human Cleavage factor Im in complex with RNA …	X-RAY DIFFRACTION	2.07
3MDG	Crystal Structure of the 25kDa Subunit of Human Cleavage factor Im in complex with RNA …	X-RAY DIFFRACTION	2.22
5R65	PanDDA analysis group deposition – Crystal Structure of HUMAN CLEAVAGE FACTOR IM in …	X-RAY DIFFRACTION	2.28
2J8Q	Crystal structure of human cleavage and polyadenylation specificity factor 5 (CPSF5) in …	X-RAY DIFFRACTION	2.3
3P5T	CFIm25-CFIm68 complex	X-RAY DIFFRACTION	2.7
3P6Y	CF Im25-CF Im68-UGUAA complex	X-RAY DIFFRACTION	2.9
3Q2S	Crystal Structure of CFIm68 RRM/CFIm25 complex	X-RAY DIFFRACTION	2.9
3Q2T	Crystal Structure of CFIm68 RRM/CFIm25/RNA complex	X-RAY DIFFRACTION	3.06

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; centriolar satellite

Antibody reliability (HPA): IH uncertain · IF supported

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)

Position	Role
55	interaction with rna
63	interaction with rna

Post-translational modifications (6)

Type	Positions
Omega-n-methylarginine	15
N6-acetyllysine	23, 29, 56
Phosphotyrosine	40
N-acetylserine	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

5 curated (TAS) of 10; 1 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-77595	Processing of Intronless Pre-mRNAs	curated
R-HSA-73856	RNA Polymerase II Transcription Termination	curated
R-HSA-72187	mRNA 3’-end processing	curated
R-HSA-9770562	mRNA Polyadenylation	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-8953854	Metabolism of RNA	—
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA	—
R-HSA-75067	Processing of Capped Intronless Pre-mRNA	—
R-HSA-73857	RNA Polymerase II Transcription	—

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 (8): 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), paraspeckles (GO:0042382)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Metabolism of RNA	2
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
Gene expression (Transcription)	1

GO top-level categories

36 GO namespaces:

Category	Terms
mRNA 3’-end processing	2
binding	2
cellular anatomical structure	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
nuclear ribonucleoprotein granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 19 of 26 annotations. The rest are phylogenetic / computational / electronic (IEA).

19 experimentally-supported GO terms:

GO term	NS	Evidence
co-transcriptional mRNA 3’-end processing, cleavage and polyadenylation pathway	BP	direct assay
mRNA 3’-end processing	BP	direct assay
mRNA alternative polyadenylation	BP	mutant phenotype
mRNA processing	BP	direct assay
protein heterotetramerization	BP	direct assay
protein tetramerization	BP	direct assay
centrosome	CC	direct assay
cytoplasm	CC	direct assay
mRNA cleavage and polyadenylation specificity factor complex	CC	direct assay
mRNA cleavage factor complex	CC	direct assay
nuclear body	CC	direct assay
nucleus	CC	direct assay
paraspeckles	CC	direct assay
RNA binding	MF	high-throughput assay
histone deacetylase binding	MF	physical interaction
identical protein binding	MF	direct assay
mRNA 3’-UTR AU-rich region binding	MF	direct assay
mRNA binding	MF	direct assay
protein homodimerization activity	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,007 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUDT21	CPSF6	Q16630	993
NUDT21	CSTF1	Q05048	809
NUDT21	CSTF2	P33240	808
NUDT21	CPSF7	Q8N684	803
NUDT21	PCF11	O94913	798
NUDT21	CPSF1	Q10570	798
NUDT21	CPSF3	Q9UKF6	784
NUDT21	CPSF2	Q9P2I0	766
NUDT21	CSTF3	Q12996	762
NUDT21	CPSF4	O95639	743
NUDT21	WDR33	Q9C0J8	739
NUDT21	SYMPK	Q92797	711
NUDT21	PABPN1	Q86U42	660
NUDT21	CSTF2T	Q9H0L4	657
NUDT21	FIP1L1	Q6UN15	631

IntAct

Human interaction partners of NUDT21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 78 partners by confidence:

Partner	Interaction type	MIscore	Records
CPSF6	direct interaction	0.890	16
CPSF7	physical association	0.740	7
MYL6	physical association	0.740	5
TRIM27	physical association	0.720	6
ATXN1	physical association	0.700	8
NTAQ1	physical association	0.560	5
IKZF1	physical association	0.560	4
FAM90A1	physical association	0.560	3
GCD7	physical association	0.560	3
GFAP	physical association	0.560	3
GOLGA2	physical association	0.560	3
KRT75	physical association	0.560	3
PRM15	physical association	0.560	3
PSPC1	physical association	0.560	3
S100PBP	physical association	0.560	3
SPAG8	physical association	0.560	3
TEPSIN	physical association	0.560	3
TRIM23	physical association	0.560	3
ZNF655	physical association	0.560	3
ZRANB1	physical association	0.560	3
CEP126	physical association	0.550	2
RBM48	physical association	0.550	2
RPLP1	physical association	0.550	2
SF3B1	physical association	0.550	1
CARM1	physical association	0.510	2
HNRNPK	association	0.460	2
SRPK1	phosphorylation reaction	0.440	1
WWOX	physical association	0.400	1
ZBTB48	physical association	0.370	2
A2M	physical association	0.370	1

BioGRID (5,611 interactions; top human partners by supporting records in a sample of 600 records): CPSF6 (Two-hybrid; 12 records), CPSF7 (Two-hybrid; 8 records), AR (Proximity Label-MS; 3 records), FXR1 (Affinity Capture-MS; 3 records), POLR2A (Affinity Capture-Western; 3 records), PSPC1 (Two-hybrid; 3 records), ACE2 (Affinity Capture-MS; 2 records), APP (Affinity Capture-MS; 2 records), BAG1 (Affinity Capture-MS; 2 records), BCL6 (Affinity Capture-MS; 2 records), BTF3 (Affinity Capture-MS; 2 records), CCNF (Proximity Label-MS; 2 records), CCNT1 (Affinity Capture-MS; 2 records), CDC42 (Reconstituted Complex; 2 records), CDC5L (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

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

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
Spliceosome, E complex	129	RBM17, DDX39A, GEMIN2, NCBP2, PRPF31, SART3, SF3A2, SNRPA, SRSF7, DDX39B, DHX15, GEMIN5, SCAF4, SMARCB1, SNRPD3, SYNCRIP, U2AF2, HNRNPC, SF3B2, SMARCC2, SFSWAP, USP39, GEMIN6, HNRNPK, RBM42, SF3B1, SF3B4, SNRPG, SRSF6, BCAS2, SMN1, CPSF7, SMARCE1, SRSF8, ARID1A, LSM4, SNRPC, CHD8, FUS, SNRNP70, SRSF11, NUDT21, PBRM1, SNRPB2, SNRPD1, YBX1, SF1, SNRPD2, SRSF2, SRSF5, PPIH, SRSF3, DDX20, SART1, SRSF1, SRSF4, PRPF19, RBM39, RBMXL2, SREK1, PRPF3, SMARCA2, U2AF1, SF3B6, SMARCA1, CPSF1, DDX23, DHX9, RUVBL1, SNRPF, SRRM2, ALYREF, HNRNPA0, HNRNPH1, PCBP2, RBM10, SF3B3, STRAP, HNRNPR, RBM25, ACTBL2, CHERP, SNRPA1, ACTL6A, DDX46, HNRNPL, RBM7, CPSF6, ARID2, DNAJC8, EFTUD2, KHSRP, RUVBL2, SMARCA4, PCBP1, SNRNP40, SNRPE, PRPF4, PRPF8, SF3A1, SF3A3, SNRNP200, ZCCHC8, DDX5, LUC7L3, SMARCC1, HNRNPA2B1, HNRNPD, HTATSF1, LUC7L2, PHF5A, PRPF6, SMARCD1, SNRPB, GEMIN8, U2SURP, NCBP1, GEMIN4, HNRNPU, MTREX, ARID1B, CHD4, HNRNPM, PRPF40A, HNRNPF, SRRT, DDX17, HNRNPA1, PUF60
CF IIAm complex (Cleavage factor IIAm complex)	16	CPSF6, DHX16, MRE11, TJP1, U2AF1, CPSF7, ERCC3, GTF2H4, NUDT21, PTBP1, SFPQ, CAPRIN1, PCF11, U2AF2, CLP1, CPSF3
CPSF6-EWSR1-ITCH-NUDT21-POLR2A-UBAP2L complex	6	CPSF6, EWSR1, ITCH, NUDT21, POLR2A, UBAP2L
CPSF6-ITCH-NUDT21-POLR2A-UBAP2L complex	5	CPSF6, ITCH, NUDT21, POLR2A, UBAP2L
CPSF6-ITCH-NUDT21-POLR2A complex	4	NUDT21, POLR2A, CPSF6, ITCH

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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 Polyadenylation	6	9.8×	9e-03
Dengue Virus-Host Interactions	8	6.8×	9e-03

Disease & clinical

Genetic variants

Variant evidence for NUDT21: 10 ClinVar records (0 pathogenic / likely pathogenic).

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 49 predictions of 481):

Position(s)	Effect	Δscore	Sites
16:56434329–56434330	donor_loss	1.0000	6
16:56434446–56434447	acceptor_loss	1.0000	6
16:56434752–56434753	donor_loss	1.0000	3
16:56439655–56439656	donor_loss	1.0000	5
16:56447787–56447788	donor_loss	1.0000	5
16:56447998	acceptor_gain	1.0000
16:56451085–56451086	donor_loss	1.0000	5
16:56434830–56434831	acceptor_loss	0.9900	6
16:56439747–56439748	acceptor_loss	0.9900	6
16:56446624–56446625	donor_loss	0.9900	6

AlphaMissense

1,156 missense substitutions predicted likely pathogenic (of 1,481 scored), across 205 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M67	9	0.930	1.000
M76	9	0.900	0.993
F47	8	1.000	1.000
D57	8	1.000	1.000
H164	8	1.000	1.000
H93	8	0.999	1.000
N190	8	0.999	1.000
H89	8	0.998	1.000
F185	8	0.998	1.000
F199	8	0.998	1.000
F64	8	0.994	1.000
F104	8	0.994	1.000
N204	8	0.994	1.000
H87	8	0.993	0.999
F103	8	0.993	1.000
D203	8	0.992	1.000
D143	8	0.984	0.999
F153	8	0.983	1.000
F224	8	0.971	0.999
D133	8	0.956	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.7e-08
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000412
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000479
Glioblastoma Multiforme (validation)	favorable	0.00064
Rectum Adenocarcinoma (TCGA)	favorable	0.000937

Disease associations

OMIM: gene MIM:604978 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724780 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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	affects expression, decreases expression, decreases methylation, increases expression, increases methylation	4
bisphenol A	affects expression, decreases expression	2
Acetaminophen	decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases 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	decreases expression, affects binding	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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for NUDT21 across ~30M SureChEMBL compounds — explore on Sugi Predict.