UPF1

Summary

UPF1 (UPF1 RNA helicase and ATPase, HGNC:9962) is a protein-coding gene on chromosome 19p13.11, encoding Regulator of nonsense transcripts 1 (Q92900). RNA-dependent helicase required for nonsense-mediated decay (NMD) of aberrant mRNAs containing premature stop codons and which modulates the expression level of normal mRNAs. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located only in the cytoplasm. When translation ends, it interacts with the protein that is a functional homolog of yeast Upf2p to trigger mRNA decapping. Use of multiple polyadenylation sites has been noted for this gene. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5976 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 224 total — 4 pathogenic, 3 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 6 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 8 tissues, sQTL in 0 (q < 0.05)
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.12 (highly constrained)
• MANE Select transcript: NM_002911
• Interaction hub: 2,914 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9962
Approved symbol	UPF1
Name	UPF1 RNA helicase and ATPase
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	HUPF1, KIAA0221, NORF1, pNORF1, smg-2
Ensembl gene	ENSG00000005007
Ensembl biotype	protein_coding
OMIM	601430
Entrez	5976

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 11 protein_coding, 7 protein_coding_CDS_not_defined, 5 retained_intron, 3 nonsense_mediated_decay

MANE Select: ENST00000262803

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 4, TSL 4: 3, TSL 5: 2

ENST00000262803, ENST00000594243, ENST00000594504, ENST00000596842, ENST00000598209, ENST00000598471, ENST00000599848, ENST00000600012, ENST00000600310, ENST00000600689, ENST00000600868, ENST00000601689, ENST00000601981, ENST00000704676, ENST00000704677, ENST00000704678, ENST00000704679, ENST00000920693, ENST00000920694, ENST00000920695, ENST00000948398, ENST00000948399, ENST00000948400, ENST00000948401, ENST00001037847, ENST00001135171

RefSeq mRNA: 2 — MANE Select: NM_002911 NM_001297549, NM_002911

CCDS: CCDS12386, CCDS74315

Canonical transcript exons

ENST00000262803 — 24 exons

Exon	Start	End
ENSE00001622662	18856186	18856300
ENSE00001764056	18854879	18855038
ENSE00001787647	18855925	18856089
ENSE00003656614	18854601	18854709
ENSE00003992120	18863438	18863612
ENSE00003992122	18850075	18850242
ENSE00003992124	18853252	18853350
ENSE00003992126	18857320	18857533
ENSE00003992127	18860826	18860982
ENSE00003992130	18862010	18862152
ENSE00003992134	18866521	18868230
ENSE00003992135	18831959	18832440
ENSE00003992139	18855124	18855242
ENSE00003992140	18847744	18847833
ENSE00003992142	18860321	18860438
ENSE00003992144	18864170	18864251
ENSE00003992146	18865289	18865450
ENSE00003992151	18866044	18866166
ENSE00003992152	18850688	18850868
ENSE00003992156	18865561	18865778
ENSE00003992158	18852135	18852296
ENSE00003992159	18856877	18857020
ENSE00003992161	18845980	18846119
ENSE00003992162	18852987	18853071

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 94.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.6167 / max 446.2443, expressed in 1823 samples.

Highest expression (Bgee): hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, mucosa of transverse colon, endometrium epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

UPF1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

8 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellum	eqtl	1.2e-04	-0.27	19:18772783:C:T
Brain Cerebellar Hemisphere	eqtl	1.5e-04	-0.30	19:18723314:C:T
Testis	eqtl	3.5e-03	+0.17	19:18823022:A:T
Thyroid	eqtl	7.4e-03	-0.37	19:17976664:C:T
Artery Tibial	eqtl	1.5e-02	-0.08	19:18714469:A:G
Pituitary	eqtl	2.6e-02	+1.10	19:19612797:T:A
Skin Sun Exposed Lower leg	eqtl	3.2e-02	-0.07	19:18591691:G:A
Brain Hypothalamus	eqtl	3.3e-02	-0.16	19:18404931:T:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
174740	31.0095	1821
174739	19.5590	1809
174741	0.0426	13
174742	0.0056	2

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	94.15	gold quality
cerebellar hemisphere	UBERON:0002245	93.86	gold quality
cerebellar cortex	UBERON:0002129	93.83	gold quality
mucosa of transverse colon	UBERON:0004991	93.72	gold quality
endometrium epithelium	UBERON:0004811	93.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.16	gold quality
granulocyte	CL:0000094	93.14	gold quality
lower esophagus mucosa	UBERON:0035834	92.98	gold quality
cerebellum	UBERON:0002037	92.93	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.41	gold quality
lower esophagus	UBERON:0013473	92.40	gold quality
skin of leg	UBERON:0001511	92.25	gold quality
adenohypophysis	UBERON:0002196	92.22	gold quality
right uterine tube	UBERON:0001302	92.03	gold quality
right testis	UBERON:0004534	92.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.00	gold quality
right lobe of thyroid gland	UBERON:0001119	91.86	gold quality
stromal cell of endometrium	CL:0002255	91.79	gold quality
pituitary gland	UBERON:0000007	91.77	gold quality
minor salivary gland	UBERON:0001830	91.77	gold quality
paraflocculus	UBERON:0005351	91.74	gold quality
left testis	UBERON:0004533	91.73	gold quality
skin of abdomen	UBERON:0001416	91.72	gold quality
esophagus	UBERON:0001043	91.71	gold quality
right lobe of liver	UBERON:0001114	91.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.65	gold quality
left lobe of thyroid gland	UBERON:0001120	91.64	gold quality
transverse colon	UBERON:0001157	91.53	gold quality
body of stomach	UBERON:0001161	91.52	gold quality
gall bladder	UBERON:0002110	91.52	gold quality
right adrenal gland	UBERON:0001233	91.38	gold quality
endocervix	UBERON:0000458	91.37	gold quality
blood	UBERON:0000178	91.35	gold quality
spleen	UBERON:0002106	91.33	gold quality
ventricular zone	UBERON:0003053	91.26	gold quality
saliva-secreting gland	UBERON:0001044	91.25	gold quality
esophagus mucosa	UBERON:0002469	91.25	gold quality
body of pancreas	UBERON:0001150	91.23	gold quality
ectocervix	UBERON:0012249	91.23	gold quality
popliteal artery	UBERON:0002250	91.22	gold quality
tibial artery	UBERON:0007610	91.21	gold quality
right adrenal gland cortex	UBERON:0035827	91.21	gold quality
left adrenal gland	UBERON:0001234	91.18	gold quality
left adrenal gland cortex	UBERON:0035825	91.11	gold quality
thyroid gland	UBERON:0002046	91.10	gold quality
metanephros cortex	UBERON:0010533	91.09	gold quality
body of uterus	UBERON:0009853	91.05	gold quality
right ovary	UBERON:0002118	90.96	gold quality
sural nerve	UBERON:0015488	90.95	gold quality
secondary oocyte	CL:0000655	90.93	gold quality
stomach	UBERON:0000945	90.92	gold quality
cerebellar vermis	UBERON:0004720	90.89	gold quality
adrenal cortex	UBERON:0001235	90.75	gold quality
aorta	UBERON:0000947	90.72	gold quality
mouth mucosa	UBERON:0003729	90.71	gold quality
adrenal gland	UBERON:0002369	90.67	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.62	gold quality
prostate gland	UBERON:0002367	90.59	gold quality
lymph node	UBERON:0000029	90.56	gold quality
right coronary artery	UBERON:0001625	90.56	gold quality
right lung	UBERON:0002167	90.54	gold quality
tonsil	UBERON:0002372	90.49	gold quality
upper lobe of left lung	UBERON:0008952	90.49	gold quality
left ovary	UBERON:0002119	90.47	gold quality
colonic epithelium	UBERON:0000397	90.43	gold quality
apex of heart	UBERON:0002098	90.35	gold quality
vagina	UBERON:0000996	90.29	gold quality
omental fat pad	UBERON:0010414	90.28	gold quality
peritoneum	UBERON:0002358	90.26	gold quality
gastrocnemius	UBERON:0001388	90.23	gold quality
left coronary artery	UBERON:0001626	90.23	gold quality
trachea	UBERON:0003126	90.22	gold quality
ascending aorta	UBERON:0001496	90.19	gold quality
adrenal tissue	UBERON:0018303	90.19	gold quality
thoracic aorta	UBERON:0001515	90.15	gold quality
sigmoid colon	UBERON:0001159	90.13	gold quality
fundus of stomach	UBERON:0001160	90.13	gold quality
nasal cavity epithelium	UBERON:0005384	90.10	gold quality
testis	UBERON:0000473	90.07	gold quality
coronary artery	UBERON:0001621	90.05	gold quality
middle temporal gyrus	UBERON:0002771	90.01	gold quality
colon	UBERON:0001155	89.92	gold quality
pancreas	UBERON:0001264	89.90	gold quality
zone of skin	UBERON:0000014	89.83	gold quality
right frontal lobe	UBERON:0002810	89.81	gold quality
muscle of leg	UBERON:0001383	89.77	gold quality
upper lobe of lung	UBERON:0008948	89.77	gold quality
middle frontal gyrus	UBERON:0002702	89.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.58	gold quality
nerve	UBERON:0001021	89.57	gold quality
tibial nerve	UBERON:0001323	89.57	gold quality
small intestine	UBERON:0002108	89.55	gold quality
left uterine tube	UBERON:0001303	89.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.43	gold quality
ganglionic eminence	UBERON:0004023	89.30	gold quality
descending thoracic aorta	UBERON:0002345	89.28	gold quality
large intestine	UBERON:0000059	89.23	gold quality
mucosa of stomach	UBERON:0001199	89.23	gold quality
intestine	UBERON:0000160	89.20	gold quality
monocyte	CL:0000576	88.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.51

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spinal cord	tissue	30.7
Corpus callosum	tissue	30.5
Cerebellum	tissue	30.4	medium
Substantia nigra	tissue	29.7
Midbrain	tissue	29.3
Superior colliculi	tissue	28.4
Medulla oblongata	tissue	28.3
Locus coeruleus	tissue	28.2
Nucleus accumbens	tissue	27.6
Ventral forebrain	tissue	27.6
Thalamus	tissue	27.3
Hypothalamus	tissue	27.2
Putamen	tissue	27.0
Septum	tissue	26.9
Hippocampus	tissue	26.8	medium
Cerebral cortex	tissue	26.6	medium
Somatosensory cortex	tissue	26.6
Basal ganglia	tissue	26.3	medium
Pons	tissue	26.2
Hippocampal formation	tissue	26.0
Periaqueductal gray	tissue	24.6
Olfactory bulb	tissue	24.6
Motor cortex	tissue	24.2
Choroid plexus	tissue	24.1
Insular cortex	tissue	23.5
Amygdala	tissue	23.3
Entorhinal cortex	tissue	23.3
Prefrontal cortex	tissue	23.1
Temporal cortex	tissue	23.0
Retrosplenial and cingulate cortex	tissue	22.3
Occipital cortex	tissue	22.3
Retrosplenial cortex	tissue	22.2
Postcentral gyrus	tissue	21.8
Vagina	tissue	21.7	medium
Pituitary gland	tissue	17.1
Caudate putamen	tissue	17.0
Frontal cortex	tissue	16.8
Stomach 1	tissue	15.5	medium
Parathyroid gland	tissue	14.8	medium
Salivary gland	tissue	13.7	medium
Pancreas	tissue	13.4	medium
Spleen	tissue	12.8	not detected
Skeletal muscle	tissue	12.0	medium
Testis	tissue	11.3	high
Adipose tissue	tissue	10.6	not detected
Appendix	tissue	10.2	medium
Placenta	tissue	9.7	medium
Thymus	tissue	9.6
Prostate	tissue	9.3	medium
Adrenal gland	tissue	9.3	medium
Colon	tissue	9.1	medium
Tongue	tissue	9.0
Small intestine	tissue	8.9	medium
Lymph node	tissue	8.5	medium
Duodenum	tissue	8.3	medium
Kidney	tissue	8.1	medium
Heart muscle	tissue	7.9	low
Thyroid gland	tissue	7.8	medium
Lung	tissue	7.6	medium
Seminal vesicle	tissue	7.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Lateral funiculus (white matter) (40.2), Nucleus ambiguus (38.9), Dorsal funiculus (white matter) (37.5), Cervical spinal cord, dorsal horn (35.7), Anterior funiculus (white matter) (33.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
NCBP1	Unknown
SLBP	Unknown

Upstream regulators (CollecTRI, top): SMG6, UPF2, ZNF268

miRNA regulators (miRDB)

Targeting UPF1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 61 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
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-6845-3P	99.94	66.88	1439
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-1912-3P	99.32	67.40	936

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.125, missense Z 6.85 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000262803 splits into 6 regions with different missense tolerance; 1 is missense-constrained (≈1% 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
19:18,832,210–18,846,025	112 / 128.2	0.87	no
19:18,846,026–18,855,161	227 / 517.9	0.44	no
19:18,855,162–18,855,199	0 / 18.0	0.00	yes (p 2.2e-05)
19:18,855,200–18,856,880	91 / 157.2	0.58	no
19:18,856,881–18,863,502	140 / 385.9	0.36	no
19:18,863,503–18,866,160	218 / 318.1	0.69	no
DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): UACC-893 (-2.397), COLO-678 (-2.148), LS1034 (-2.027), HCC1143 (-2.023), COLO-320 (-2.015), SNU-5 (-1.981), HCC-56 (-1.94), AsPC-1 (-1.938), TUHR10TKB (-1.937), SNU-213 (-1.93), NCI-H2122 (-1.925), SNU-1076 (-1.901), SW837 (-1.9), ST486 (-1.881), MFE-280 (-1.868).

Literature-anchored findings (GeneRIF, showing 40)

• inhibition of rent1/hUpf1 expression abrogated both nonsense-mediated mRNA decay and nonsense-mediated altered splicing of nonsense T cell receptor beta transcripts; rent1/hUpf1 enters the nucleus where it may influence early events in mRNA biogenesis (PMID:12228722)
• Dcp1a and Dcp2 interact with the nonsense-mediated decay factor Upf1 (PMID:12417715)
• Data show that phosphorylated hUPF1, the human ortholog of UPF1/SMG-2, forms a complex with human orthologs of the Caenorhabditis elegans proteins SMG-5 and SMG-7. (PMID:14636577)
• regulated degradation of histone mRNAs requires Upf1, a key regulator of the nonsense-mediated decay pathway, and ataxia telangiectasia and Rad3 related, a key regulator of the DNA damage checkpoint pathway activated during replication stress (PMID:16086026)
• During nonsense-mediated mRNA decay, CBP80 interacts with Upf1 and promotes the interaction of Upf1 with Upf2 but not with Stau1. (PMID:16186820)
• Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD (PMID:16452507)
• REVIEW. the direct roles of UPF1 and other NMD-factors in DNA replication and genome maintenance pathways and suggest functional connections between RNA and DNA metabolism (PMID:16861888)
• 3 A resolution crystal structure of the highly conserved cysteine-histidine-rich domain (PMID:16931876)
• analysis of how ATP binding destabilizes ssRNA binding to Upf1p (PMID:17159905)
• The Upf complex communicates with the exon-junction complex and triggers nonsense-mediated decay in the cytoplasm. (PMID:17803942)
• UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1. (PMID:18066079)
• suggests a regulatory pathway by a combination of ADAR1 A-to-I editing enzyme and RNA degradation presumably with the aid of hUpf1 (PMID:18362360)
• overexpression of UPF1 led to a dramatic up-regulation of HIV-1 expression at the RNA and protein synthesis levels (PMID:18369187)
• Study provides evidence that phospho-Upf1 functions after nonsense codon recognition during steps that involve the translation initiation factor eIF3 and mRNA decay factors (PMID:18423202)
• The nonsense-mediated-decay mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. (PMID:18427545)
• Results demonstrate that the mammalian gene ZNF268 is regulated by hUpf1 via its promoter. (PMID:18774934)
• The authors propose that the bipartite mode of UPF2 binding to UPF1 brings the ribosome and the exon junction complex in close proximity by forming a tight complex after an initial weak encounter with either element. (PMID:19556969)
• hUPF1 may participate in RNA silencing by facilitating the binding of the RNA-induced silencing complex to the target and by accelerating the decay of the mRNA. (PMID:19704008)
• UPF1 binds PTC-containing mRNA more efficiently than the corresponding PTC-free mRNA in a way that is promoted by the UPF1-CBP80 interaction. (PMID:20691628)
• A conserved nonsense-mediated mRNA decay event within HNRNPA2B1 that appears to mediate autoregulation of HNRNPA2B1 expression levels, was identified upon UPF1 knockdown . (PMID:20946641)
• Study uncovers a 2-step mechanism for Upf1-dependent degradation of mRNAs with long 3’UTRs and proposes a model for 3’UTR length surveillance in which equilibrium binding of Upf1 to mRNAs precedes a kinetically distinct commitment to RNA decay. (PMID:21029861)
• demonstrate that the ATPase activity of the RNA helicase Upf1 allows disassembly of mRNPs undergoing nonsense-mediated mRNA decay (PMID:21145460)
• Data show that upon binding to Upf2, the regulatory CH domain of Upf1 undergoes a large conformational change, causing the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity. (PMID:21419344)
• hUPF1 rescues the toxicity of FUS/TLS in yeast model, implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. (PMID:21541368)
• Rescue of UPF1 by expression of exogenous UPF1 was found to suppress vascular smooth muscle cell proliferation. (PMID:21749700)
• UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication (PMID:21829167)
• Recruitment of Stau2 alone or in combination with Upf1 differentially affects the fate of mRNAs. (PMID:22087843)
• the functions of UPF1 in maintaining the stability of telomeres and of the genome (PMID:22156744)
• The heptameric assembly of the UPF complex is built around UPF2, a scaffold protein with a ring structure that closes around the CH domain of UPF1, keeping the helicase region in an accessible and unwinding-competent state. (PMID:22522823)
• HTLV-1 Tax binds to UPF1 and causes an increase in the amount of phospho-UPF1. These activities coincidewith an enhanced localization of UPF1 in the P-bodies, in which Tax was also partially detected (PMID:22553336)
• UPF1 is an important factor for the RNA quality control system and the regulation of physiological gene expression, and contributes to DNA replication, DNA repair, telomere metabolism, and stabilization of HIV-1 genomic RNA. (PMID:22622014)
• Data show that UPF1 also interacts with proteins associated with nuclear RNA degradation and transcription termination (PMID:22817733)
• Data indicate a specific impact of hUPF1 on the regulation of complex I genes. (PMID:22889941)
• The SQ domain of the human Upf1 helicase, directly interacts with the helicase domain to impede ATP hydrolysis and RNA unwinding. (PMID:23275559)
• nonsense-mediated mRNA decay involves UPF1 binding along a 3’ UTR whether the 3’ UTR contains an exon-junction complex. (PMID:23404710)
• UPF1 is a critical gene expression regulator of 5-lipoxygenase and other proteins in the monocytes. (PMID:23642263)
• Thus, whereas ectopic MOV10 restricts human immunodeficiency virus type 1 replication, the related UPF1 helicase functions as a cofactor at an early postentry step. (PMID:23785196)
• MARVELD1 substantially inhibits nonsense-mediated RNA decay by decreasing the pioneer round of translation but not steady-state translation, and is an important component of the molecular machinery containing UPF1 and Y14. MARVELD1 promotes the dissociation of SMG1 from UPF1, resulting in the repression of serine phosphorylation of UPF1, and subsequently blocks the recruitment of SMG5. (PMID:23826386)
• UPF1 binds RNA before translation and gets displaced from the coding regions by translating ribosomes. (PMID:23832275)
• FXR1 and UPF1 may have a functional role in prostate cancer progression and metastasis. (PMID:23881279)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	upf1	ENSDARG00000016302
mus_musculus	Upf1	ENSMUSG00000058301
rattus_norvegicus	Upf1	ENSRNOG00000020134
drosophila_melanogaster	Upf1	FBGN0030354
caenorhabditis_elegans	smg-2	WBGENE00004880

Paralogs (10): AQR (ENSG00000021776), MOV10L1 (ENSG00000073146), SETX (ENSG00000107290), ZNFX1 (ENSG00000124201), HELZ2 (ENSG00000130589), IGHMBP2 (ENSG00000132740), DNA2 (ENSG00000138346), MOV10 (ENSG00000155363), CT55 (ENSG00000169551), HELZ (ENSG00000198265)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107995) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal embryo development	1
increased apoptosis	1
empty decidua capsularis	1
embryonic lethality between implantation and somite formation, complete penetrance	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	Q0V8H6	92.1%	Diamond
Takifugu rubripes	Q98TR3	88.0%	Diamond
Mesocricetus auratus	Q60560	87.6%	Diamond
Xenopus tropicalis	F6QXW0	82.9%	Diamond
Xenopus laevis	Q8QHA5	82.9%	Diamond
Arabidopsis thaliana	Q9FJR0	71.9%	Diamond
Neurospora crassa OR74A	Q9HEH1	67.3%	Diamond
Schizosaccharomyces pombe 972h-	Q09820	61.8%	Diamond
Saccharomyces cerevisiae S288C	P30771	57.9%	Diamond
Dictyostelium discoideum	Q54I89	54.4%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q57568	35.8%	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
COPE	protein-coding	11316
COMP	protein-coding	1311
GDF1	protein-coding	2657
DDX49	protein-coding	54555
HOMER3-AS1	ncRNA	102724360
CERS1	protein-coding	10715
HOMER3	protein-coding	9454
CRTC1	protein-coding	23373
KLHL26	protein-coding	55295

Protein

Protein identifiers

Regulator of nonsense transcripts 1 — Q92900 (reviewed: Q92900)

Alternative names: ATP-dependent helicase RENT1, Double-stranded nucleic acid 5’-3’ helicase UPF1, Nonsense mRNA reducing factor 1, Up-frameshift suppressor 1 homolog

All UniProt accessions (5): Q92900, A0A024R7L5, A0A994J4L7, A0A994J597, A0A994J773

UniProt curated annotations — full annotation on UniProt →

Function. RNA-dependent helicase required for nonsense-mediated decay (NMD) of aberrant mRNAs containing premature stop codons and which modulates the expression level of normal mRNAs. ATP-dependent 5’-3’ helicase active on RNA:DNA substrates with a 5’-RNA extension. ATP-dependent 5’-3’ helicase active on RNA:RNA substrates with a 5’-RNA extension. ATP-dependent 5’-3’ helicase active on DNA:DNA substrates with a 5’-DNA extension. Is recruited to mRNAs upon translation termination and undergoes a cycle of phosphorylation and dephosphorylation; its phosphorylation appears to be a key step in NMD. Recruited by release factors to stalled ribosomes together with the SMG1C protein kinase complex to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) (located 50-55 or more nucleotides downstream from the termination codon) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Phosphorylated UPF1 is recognized by EST1B/SMG5, SMG6 and SMG7 which are thought to provide a link to the mRNA degradation machinery involving exonucleolytic and endonucleolytic pathways, and to serve as adapters to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation and allowing the recycling of NMD factors. UPF1 can also activate NMD without UPF2 or UPF3, and in the absence of the NMD-enhancing downstream EJC indicative for alternative NMD pathways. Plays a role in replication-dependent histone mRNA degradation at the end of phase S; the function is independent of UPF2. For the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed. The ATPase activity of UPF1 is required for disassembly of mRNPs undergoing NMD. Together with UPF2 and dependent on TDRD6, mediates the degradation of mRNA harboring long 3’UTR by inducing the NMD machinery. Has ssDNA-stimulated ATPase activity (poly(dT) and poly(dA) are most stimulatory). Binds RNA; addition of ATP decreases RNA-binding.

Subunit / interactions. Monomeric in solution. Forms a trimeric UPF complex where UPF2 bridges UPF1 and UPF3B; UPF2 contacts the N-terminal CH-rich domain of UPF1 and the N-terminus of UPF3B. The trimeric UPF complex interacts with the EJC core complex. Found in a post-splicing messenger ribonucleoprotein (mRNP) complex. Associates with the exon junction complex (EJC). Associates with the SGM1C complex; is phosphorylated by the complex kinase component SGM1. Part of a complex composed of SMG1, DHX34 and UPF1; within the complex DHX34 acts as a scaffolding protein to facilitate SMG1 phosphorylation of UPF1. Interacts with UPF2 via the CH-rich domain. Interacts with UPF3A and UPF3B. Interacts with EST1A. Interacts with SLBP. Interacts (when hyperphosphorylated) with PNRC2. Interacts with AGO1 and AGO2. Interacts with GSPT2. Interacts with isoform 1 and isoform 5 of ADAR/ADAR1. Interacts with SMG7. Interacts with ZC3H12A; this interaction occurs in a mRNA translationally active- and termination-dependent manner and is essential for ZC3H12A-mediated degradation of target mRNAs. Interacts with CPSF6. Interacts with MOV10; the interaction is direct and RNA-dependent. Interacts with SHFL; the interaction increases in the presence of RNA. Interacts with UPF2 and DDX4; interactions are mediated by TDRD6. Interacts with DHX34 and PABPC1/PABP1; the interactions are RNA-independent. Interacts with RBM46. (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein Tax; this interaction inhibits the host nonsense-mediated mRNA decay (NMD).

Subcellular location. Cytoplasm. P-body. Nucleus. Perinuclear region.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated by SMG1; required for formation of mRNA surveillance complexes.

Activity regulation. The helicase domain is maintained in an inactive state by intramolecular interactions with its N- and C-terminal domains. UPF2 and UPF3B together stimulate both the ATPase and 5’-3’ RNA:DNA helicase activities of this protein. UPF2 alone stimulates the ATPase and 5’-3’ RNA:DNA helicase activities of UPF1 missing the CH-rich domain. The N-terminal CH-rich domain inhibits the 5’-3’ helicase activity. The C-terminal SQ domain also inhibits the 5’-3’ helicase activity.

Cofactor. Binds 1 Mg(2+) ions per subunit. Binds 3 Zn(2+) per subunit.

Domain organisation. The CH-rich domain contacts UPF2 and inhibits both the ATPase and 5’-3’ RNA:DNA helicase activities of this protein. It increases RNA-binding by the helicase domain. The isolated CH-rich domain has no RNA-binding or ATPase activity. Comparison with a yeast structure that includes the CH-rich domain suggests the CH-rich domain docks RNA into the protein, increasing RNA binding and thus decreasing ATPase activity. The CH-rich domain probably binds to the same region of UPF1 as UPF2. Deletion of the CH-rich domain increases ATPase activity and 5’-3’ helicase activity dramatically. Helicase activity (of the isolated helicase domain (HD) or the HD plus the CH-rich domain) is slow but highly processive, capable of translocating on ssDNA, may be able to unwind over 10 kb of dsDNA, and translocates through protein-bound sequences, allowing it to remodel ribonucleoprotein complexes. The two helicase domains face each other and sandwich ATP at one end of the molecule; they form an interface which binds extended RNA at the other end of protein. The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family. The SQ domain (serine-glutamine clusters) inhibits the 5’-3’ RNA:DNA helicase, ATPase and RNA-binding activities of this protein; deletion of the SQ domain increases helicase activity about 6-fold. Protein phosphorylation does not prevent the SQ domain from inhibiting the helicase activity.

Similarity. Belongs to the DNA2/NAM7 helicase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92900-1	1	yes
Q92900-2	2

RefSeq proteins (2): NP_001284478, NP_002902* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006935	Helicase/UvrB_N	Domain
IPR018999	UPF1_CH/ZBD	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR040812	UPF1_1B_dom	Domain
IPR041677	DNA2/NAM7_AAA_11	Domain
IPR041679	DNA2/NAM7-like_C	Domain
IPR045055	DNA2/NAM7-like	Family
IPR047187	SF1_C_Upf1	Domain

Pfam: PF04851, PF09416, PF13086, PF13087, PF18141

Enzyme classification (BRENDA)

• EC 5.6.2.5 — RNA 5’-3’ helicase (BRENDA: 8 organisms, 31 substrates, 19 inhibitors, 2 Km, 1 kcat entries)
• EC 5.6.2.6 — RNA 3’-5’ helicase (BRENDA: 31 organisms, 218 substrates, 75 inhibitors, 53 Km, 26 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	—	33
GTP	0.09–0.35	11
ATP	0.0092	1

Catalyzed reactions (Rhea)

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (184 total): helix 43, strand 42, binding site 27, mutagenesis site 24, turn 12, region of interest 9, modified residue 9, sequence conflict 6, compositionally biased region 4, domain 3, short sequence motif 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

12 structures by resolution:

PDB	Title	Method	Resolution (Å)
2XZO	Upf1 helicase - RNA complex	X-RAY DIFFRACTION	2.4
2GK6	Structural and Functional insights into the human Upf1 helicase core	X-RAY DIFFRACTION	2.4
2WJY	Crystal structure of the complex between human nonsense mediated decay factors UPF1 and …	X-RAY DIFFRACTION	2.5
2GJK	Structural and functional insights into the human Upf1 helicase core	X-RAY DIFFRACTION	2.6
8RXB	Human UPF1 CH domain in complex with SMG6 peptide	X-RAY DIFFRACTION	2.6
2XZP	Upf1 helicase	X-RAY DIFFRACTION	2.72
2GK7	Structural and Functional insights into the human Upf1 helicase core	X-RAY DIFFRACTION	2.8
2WJV	Crystal structure of the complex between human nonsense mediated decay factors UPF1 and …	X-RAY DIFFRACTION	2.85
2IYK	Crystal structure of the UPF2-interacting domain of nonsense mediated mRNA decay factor …	X-RAY DIFFRACTION	2.95
6Z3R	Structure of SMG1-8-9 kinase complex bound to UPF1-LSQ	ELECTRON MICROSCOPY	2.97
6EJ5	A conserved structural element in the RNA helicase UPF1 regulates its catalytic activity …	X-RAY DIFFRACTION	3.34
9QWN	Human UPF1 in complex with the histone stem loop RNA	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92900-F1	73.58	0.42

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH approved · 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.

Ligand- & substrate-binding residues (27)

Position	Role
123	Zn(2+)
126	Zn(2+)
137	Zn(2+)
140	Zn(2+)
145	Zn(2+)
155	Zn(2+)
159	Zn(2+)
165	Zn(2+)
183	Zn(2+)
186	Zn(2+)
209	Zn(2+)
213	Zn(2+)
480	ATP
481	ATP
486	ATP
506	ATP
507	ATP
508	ATP
509	ATP
510	ATP
510	Mg(2+)
511	ATP
676	ATP
713	ATP
714	ATP
844	ATP
876	ATP

Post-translational modifications (9)

Type	Positions
Phosphoserine	10, 31, 565, 956, 1089, 1107, 1110, 1127
Omega-n-methylarginine	1019

Mutagenesis-validated functional residues (24)

Position	Phenotype
126	abolishes ability to interact with upf2/rent2 and copurifies with greater amounts of smg1, smg8 and smg9. increases interaction with dhx34 …
181–184	abolishes interaction with upf2. decreases interaction with dhx34.
192	increases atpase activity of whole protein, upf2 does not stimulate atpase activity. prevents the ch-rich domain from inhibiting helicase …
204–205	abolishes interaction with upf2. no effect on interaction with dhx34.
506–508	prevents dephosphorylation and targets the protein to the p-body.
506	decreases interaction with dhx34; when associated with e-508.
508	decreases interaction with dhx34; when associated with r-506.
509	inhibits histone mrna degradation, atpase activity and atp binding. no effect on interaction with dhx34.
610–611	impairs rna binding.
615	impairs rna binding.
647–648	loss of atpase activity and dna helicase activity.
647–648	loss of atpase activity and helicase activity. inhibits zc3h12a-mediated il6 mrna degradation.
676	impairs atpase activity, no effect on atp binding.
714	impairs atpase activity and atp binding.
843	inhibits histone mrna degradation.
843	abolishes nmd.
876	impairs atpase activity and atp binding.
1084	impairs association with upf2, smg1 and smg7 and impairs phosphorylation; when associated with a-1089, a-1107 and a-1127.
1089	impairs association with upf2, smg1 and smg7 and impairs phosphorylation; when associated with a-1084, a-1107 and a-1127.
1089	still phosphorylated but with less efficiency.
1107	impairs association with upf2, smg1 and smg7 and impairs phosphorylation; when associated with a-1084, a-1089 and a-1127.
1107	impairs phosphorylation.
1108	impairs phosphorylation.
1127	impairs association with upf2, smg1 and smg7 and impairs phosphorylation; when associated with a-1084, a-1089 and a-1107.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	curated
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	curated
R-HSA-8953854	Metabolism of RNA	—
R-HSA-927802	Nonsense-Mediated Decay (NMD)	—

MSigDB gene sets: 218 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_TELOMERE_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_TRANSLATIONAL_TERMINATION, GOBP_TRANSLATION

GO Biological Process (19): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), nuclear-transcribed mRNA catabolic process (GO:0000956), DNA replication (GO:0006260), DNA repair (GO:0006281), mRNA export from nucleus (GO:0006406), regulation of translational termination (GO:0006449), telomere maintenance via semi-conservative replication (GO:0032201), regulation of telomere maintenance (GO:0032204), cell cycle phase transition (GO:0044770), positive regulation of mRNA catabolic process (GO:0061014), 3’-UTR-mediated mRNA destabilization (GO:0061158), histone mRNA catabolic process (GO:0071044), cellular response to lipopolysaccharide (GO:0071222), cellular response to interleukin-1 (GO:0071347), regulation of gene expression (GO:0010468), RNA surveillance (GO:0071025), positive regulation of mRNA metabolic process (GO:1903313), negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:2000623), positive regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:2000624)

GO Molecular Function (16): chromatin binding (GO:0003682), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), helicase activity (GO:0004386), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), double-stranded DNA helicase activity (GO:0036121), telomeric repeat DNA binding (GO:0042162), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), exon-exon junction complex (GO:0035145), supraspliceosomal complex (GO:0044530), perinuclear region of cytoplasm (GO:0048471), cytoplasmic ribonucleoprotein granule (GO:0036464)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Nonsense-Mediated Decay (NMD)	2
Metabolism of RNA	1

GO top-level categories

showing 60 of 67 GO namespaces:

Category	Terms
cellular anatomical structure	5
binding	3
cytoplasm	3
nuclear-transcribed mRNA catabolic process	2
mRNA catabolic process	2
DNA metabolic process	2
gene expression	2
telomere maintenance	2
cell cycle process	2
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	2
regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	2
nucleic acid binding	2
helicase activity	2
ATP-dependent activity	2
DNA biosynthetic process	1
DNA damage response	1
RNA export from nucleus	1
mRNA transport	1
translational termination	1
regulation of translation	1
regulation of protein-containing complex disassembly	1
nuclear DNA replication	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
positive regulation of catabolic process	1
regulation of mRNA catabolic process	1
positive regulation of mRNA metabolic process	1
mRNA destabilization	1
histone mRNA metabolic process	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to interleukin-1	1
cellular response to cytokine stimulus	1
regulation of macromolecule biosynthetic process	1
RNA catabolic process	1
mRNA metabolic process	1
positive regulation of RNA metabolic process	1
regulation of mRNA metabolic process	1
negative regulation of mRNA catabolic process	1
positive regulation of mRNA catabolic process	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
DNA helicase activity	1
sequence-specific DNA binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ATP-dependent activity, acting on DNA	1
catalytic activity	1
cation binding	1
chromosomal region	1
chromosome	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 25 of 46 annotations. The rest are phylogenetic / computational / electronic (IEA).

25 experimentally-supported GO terms:

GO term	NS	Evidence
3’-UTR-mediated mRNA destabilization	BP	direct assay
DNA repair	BP	direct assay
DNA replication	BP	mutant phenotype
cell cycle phase transition	BP	mutant phenotype
histone mRNA catabolic process	BP	mutant phenotype
nuclear-transcribed mRNA catabolic process	BP	mutant phenotype
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	BP	direct assay
positive regulation of mRNA catabolic process	BP	direct assay
regulation of telomere maintenance	BP	mutant phenotype
regulation of translational termination	BP	mutant phenotype
telomere maintenance via semi-conservative replication	BP	direct assay
chromatin	CC	direct assay
chromosome, telomeric region	CC	direct assay
cytosol	CC	direct assay
exon-exon junction complex	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
supraspliceosomal complex	CC	direct assay
ATP hydrolysis activity	MF	direct assay
RNA binding	MF	direct assay
RNA helicase activity	MF	direct assay
chromatin binding	MF	direct assay
double-stranded DNA helicase activity	MF	direct assay
protein-containing complex binding	MF	physical interaction
telomeric repeat DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,914 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UPF1	UPF2	Q9HAU5	996
UPF1	SMG5	Q9UPR3	979
UPF1	UPF3A	Q9H1J1	978
UPF1	UPF3B	Q9BZI7	974
UPF1	SMG7	Q92540	974
UPF1	SMG6	Q86US8	965
UPF1	SMG1	Q96Q15	964
UPF1	SMG9	Q9H0W8	949
UPF1	SMG8	Q8ND04	937
UPF1	STAU1	O95793	898
UPF1	XRN1	Q8IZH2	897
UPF1	DCP2	Q8IU60	887
UPF1	ETF1	P46055	882
UPF1	GSPT1	P15170	873
UPF1	DCP1A	Q9NPI6	865

IntAct

Human interaction partners of UPF1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 50 partners by confidence:

Partner	Interaction type	MIscore	Records
UPF2	association	0.960	22
UPF3B	association	0.890	6
DCP1A	physical association	0.780	7
STAU1	physical association	0.780	6
CASC3	association	0.770	1
SMG1	association	0.760	2
RBM8A	association	0.730	1
GSPT2	physical association	0.680	2
DCP2	association	0.640	3
PABPC1	association	0.640	1
PNRC2	physical association	0.620	8
SMG7	physical association	0.620	3
FAM120A	physical association	0.620	1
DDX6	colocalization	0.590	1
L1RE1	physical association	0.580	1
GSPT1	physical association	0.560	2
SZRD1	physical association	0.560	1
UPF3A	physical association	0.560	1
ALYREF	association	0.530	1
ACD	physical association	0.520	3
ADAR	physical association	0.520	3
TERT	physical association	0.520	3
SLBP	association	0.500	3
EIF4E	association	0.460	1
SKI7	physical association	0.400	2
DEK	physical association	0.400	1
INTS6	physical association	0.400	1
NDRG1	physical association	0.400	1
PNRC1	physical association	0.370	2
CSNK2B	physical association	0.370	1

BioGRID (870 interactions; top human partners by supporting records in a sample of 600 records): UPF2 (Affinity Capture-Western; 9 records), UPF3B (Affinity Capture-MS; 7 records), ILF2 (Affinity Capture-MS; 5 records), FAM120A (Proximity Label-MS; 4 records), SMG1 (Biochemical Activity; 4 records), STAU1 (Affinity Capture-MS; 4 records), DCP2 (Affinity Capture-Western; 3 records), FBL (Proximity Label-MS; 3 records), HIST1H1A (Affinity Capture-MS; 3 records), HNRNPA1 (Affinity Capture-MS; 3 records), IGF2BP1 (Proximity Label-MS; 3 records), MEMO1 (Affinity Capture-MS; 3 records), NIFK (Affinity Capture-MS; 3 records), PABPC1 (Affinity Capture-MS; 3 records), PRR11 (Affinity Capture-MS; 3 records)

SIGNOR signaling

showing 9 of 11 signaling interactions:

A	Effect	B	Mechanism
SMG1	up-regulates	UPF1	phosphorylation
MOV10	“up-regulates activity”	UPF1	binding
UPF1	“form complex”	Upf-EJC	binding
AKT2	“up-regulates activity”	UPF1	phosphorylation
AKT3	“up-regulates activity”	UPF1	phosphorylation
AKT1	“up-regulates activity”	UPF1	phosphorylation
ATR	“up-regulates activity”	UPF1	phosphorylation
UPF2	“up-regulates activity”	UPF1	binding
UPF3B	“up-regulates activity”	UPF1	binding

Protein complexes (CORUM) (6)

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

6 complexes by size:

Complex	Subunits	Members
mRNA decay complex (UPF1, UPF2, UPF3B, DCP2, XRN1, XRN2, EXOSC2, EXOSC4, EXOSC10, PARN)	10	XRN1, XRN2, DCP2, EXOSC2, EXOSC4, PARN, UPF1, UPF3B, EXOSC10, UPF2
Postsplicing complex	7	NXF1, RBM8A, RNPS1, UPF1, UPF2, UPF3A, UPF3B
★ DCP1A-NR3C1-PNRC2-UPF1 complex	4	DCP1A, NR3C1, PNRC2, UPF1
SURF complex	4	ETF1, GSPT1, SMG1, UPF1
Upf complex (UPF1, UPF2, UPF3a)	3	UPF1, UPF2, UPF3A
Upf complex (UPF1, UPF2, UPF3b)	3	UPF1, UPF2, UPF3B

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	14	35.0×	1e-16
mRNA 3’-end processing	6	30.3×	2e-06
Transport of Mature mRNA derived from an Intron-Containing Transcript	7	27.3×	3e-07
Regulation of expression of SLITs and ROBOs	10	17.8×	1e-08
Processing of Capped Intron-Containing Pre-mRNA	5	10.5×	2e-03
mRNA Splicing - Major Pathway	7	9.8×	2e-04
Metabolism of RNA	7	7.5×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	14	145.6×	9e-26
mRNA export from nucleus	8	52.6×	2e-10
mRNA splicing, via spliceosome	6	12.2×	5e-04
translation	5	11.4×	2e-03

Disease & clinical

Genetic variants

Variant evidence for UPF1: 224 ClinVar records (7 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	136
Likely benign	34
Benign	22

Top pathogenic / likely-pathogenic (7)

Showing all 7 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3341108	NM_002911.4(UPF1):c.1984G>A (p.Asp662Asn)	Pathogenic	criteria provided, single submitter	1
3341109	NM_002911.4(UPF1):c.949_951del (p.Asp317del)	Pathogenic	criteria provided, single submitter	1
4537885	NM_002911.4(UPF1):c.2804A>G (p.Tyr935Cys)	Pathogenic	criteria provided, single submitter	1
4689802	NM_002911.4(UPF1):c.1774G>A (p.Glu592Lys)	Pathogenic	criteria provided, single submitter	1
930204	NM_002911.4(UPF1):c.2489A>G (p.Gln830Arg)	Likely pathogenic	criteria provided, single submitter	1
4827887	NM_002911.4(UPF1):c.2246A>G (p.Tyr749Cys)	Likely pathogenic	criteria provided, single submitter	1
4891419	NM_002911.4(UPF1):c.2572C>T (p.Arg858Cys)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore UPF1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 1,903):

Position(s)	Effect	Δscore	Sites
19:18846120–18846121	donor_loss	1.0000	5
19:18847742	acceptor_loss	1.0000	3
19:18847831	donor_gain	1.0000
19:18847834–18847835	donor_loss	1.0000	5
19:18850066–18850067	acceptor_gain	1.0000	2
19:18850073–18850074	acceptor_loss	1.0000	5
19:18850243	donor_loss	1.0000
19:18850686–18850687	acceptor_loss	1.0000	6
19:18850866	donor_gain	1.0000
19:18852133–18852134	acceptor_loss	1.0000	6

AlphaMissense

4,646 missense substitutions predicted likely pathogenic (of 7,342 scored), across 948 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
M715	9	0.996	1.000
M434	9	0.993	0.999
M682	9	0.879	0.990
D647	8	1.000	1.000
D673	8	1.000	1.000
D838	8	1.000	1.000
H155	8	0.999	1.000
F863	8	0.999	1.000
D298	8	0.998	1.000
D539	8	0.998	1.000
N777	8	0.998	1.000
H159	8	0.996	1.000
F192	8	0.996	1.000
D317	8	0.996	0.999
D371	8	0.996	0.999
D602	8	0.996	0.999
D633	8	0.996	0.999
H674	8	0.996	0.999
F727	8	0.996	1.000
N871	8	0.996	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.83e-07
Skin Cutaneous Melanoma (TCGA)	unfavorable	0.000244

Disease associations

OMIM: gene MIM:601430 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodevelopmental disorder	Strong	Autosomal dominant	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green

Mondo (3): strabismus (MONDO:0003432), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

GWAS associations

1 associations:

Study	Trait	p-value
GCST010222_2	Attention deficit hyperactivity disorder	3e-6

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D013285	Strabismus	C10.292.562.887; C11.590.810

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066487 (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
7.62	Kd	24.29	nM	CHEMBL5653589
7.62	ED50	24.29	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2149734: Binding affinity to human UPF1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0243	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects binding, decreases reaction, decreases expression, increases expression	4
bisphenol A	affects methylation, decreases expression, increases expression	3
bisphenol S	decreases methylation, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Smoke	increases expression, decreases expression, increases abundance	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases methylation	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
antibiotic G 418	affects localization	1
afimoxifene	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
amlexanox	affects localization	1
jasplakinolide	affects localization, affects binding, decreases reaction	1
K 7174	decreases expression	1
torcetrapib	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Antineoplastic Agents, Immunological	decreases response to substance, increases expression	1
Arsenic	affects methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652776	Binding	Binding affinity to human UPF1 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.

showing 60 of 510 trials:

NCT	Phase	Status	Title
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00152750	Phase 4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	Phase 4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	Phase 4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	Phase 4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	Phase 4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	Phase 4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	Phase 4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	Phase 4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	Phase 4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	Phase 4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	Phase 4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	Phase 4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	Phase 4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	Phase 4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	Phase 4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	Phase 4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	Phase 4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	Phase 4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	Phase 4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	Phase 4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	Phase 4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	Phase 4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	Phase 4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	Phase 4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	Phase 4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	Phase 4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	Phase 4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	Phase 4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	Phase 4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	Phase 4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	Phase 4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	Phase 4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	Phase 4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	Phase 4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	Phase 4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	Phase 4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory
NCT00536419	Phase 4	UNKNOWN	Impact of Attention Deficit/Hyperactivity Disorder and Substance Use Disorder on Motorcycle Traffic Accidents
NCT00546910	Phase 4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00552266	Phase 4	UNKNOWN	Methylphenidate in ADHD With Trichotillomania
NCT00564954	Phase 4	COMPLETED	A Study of Dex-methylphenidate Extended Release in Children (6-12 Years) With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00566371	Phase 4	COMPLETED	The Effect of a Once Daily Dose of Atomoxetine (ATX) on ADHD-Related Insomnia in Children and Adolescents
NCT00573534	Phase 4	COMPLETED	Pilot Study of Vyvanse™ In ADHD Adolescents at Risk for Substance Abuse
NCT00585910	Phase 4	COMPLETED	Study of Atomoxetine and OROS Methylphenidate to Treat Children and Adolescents Ages 6-17 With ADHD
NCT00586157	Phase 4	COMPLETED	Study of Medication Patch to Treat Children Ages 6-12 With ADHD
NCT00586573	Phase 4	COMPLETED	Open-Label Pilot Study of Namenda in Adult Subjects With ADHD and ADHD NOS
NCT00593112	Phase 4	COMPLETED	Proton Magnetic Spectroscopy in Children and Adolescents With ADHD Before and After Treatment With OROS Methylphenidate
NCT00607919	Phase 4	COMPLETED	Treatment of ADHD With Atomoxetine in Children & Adolescents With ADHD & Comorbid Dyslexia
NCT00663442	Phase 4	COMPLETED	Basic and Clinical Research on Attention Deficit Hyperactivity Disorder (ADHD)
NCT00687609	Phase 4	TERMINATED	Pilot Evaluation of Atomoxetine on Attention Deficit Hyperactivity Disorder (ADHD) Symptoms in Adolescents With Cannabis abusE
NCT00716274	Phase 4	COMPLETED	Effects of Atomoxetine on Brain Activation During Attention & Reading Tasks in Participants With ADHD & Comorbid Dyslexia
NCT00733356	Phase 4	COMPLETED	The Effects of Vyvanse(TM) on Brain Hemodynamics and Reading
NCT00753012	Phase 4	COMPLETED	Cardiovascular Study of Lisdexamfetamine in Healthy and Hypertensive Attention Deficit Hyperactivity Disorder Adults
NCT00754208	Phase 4	COMPLETED	Long Acting Stimulant Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Young Children
NCT00760747	Phase 4	COMPLETED	Comparison of Slow and Fast Transition From Stimulants to Atomoxetine in Children and Adolescents With Attention Deficit/Hyperactivity Disorder(ADHD)
NCT00770627	Phase 4	UNKNOWN	Clinical Trial to Evaluate the Efficacy and the Tolerance of an Omega 3 Fatty Acids Supplementation in ADHD Children
NCT00783835	Phase 4	COMPLETED	Study to Evaluate the Efficacy and Quality of Life of Long-Acting Methylphenidate in Adults With Attention Deficit Hyperactivity Disorder (ADHD)
NCT00799409	Phase 4	COMPLETED	Lab School Day Study for CONCERTA of Older Children With ADHD
NCT00799487	Phase 4	COMPLETED	CONCERTA Lab School Study

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for UPF1 across ~30M SureChEMBL compounds — explore on Sugi Predict.