USP21

Summary

USP21 (ubiquitin specific peptidase 21, HGNC:12620) is a protein-coding gene on chromosome 1q23.3, encoding Ubiquitin carboxyl-terminal hydrolase 21 (Q9UK80). Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator.

This gene encodes a member of the C19 peptidase family, also known as family 2 of ubiquitin carboxy-terminal hydrolases. The encoded protein cleaves ubiquitin from ubiquitinated proteins for recycling in intracellular protein degradation. The encoded protein is also able to release NEDD8, a ubiquitin-like protein, from NEDD8-conjugated proteins. This gene has been referred to as USP16 and USP23 but is now known as USP21. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27005 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 90 total
• GTEx eGene: eQTL in 6 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.67 (unconstrained)
• MANE Select transcript: NM_001014443
• Notable: 90 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12620
Approved symbol	USP21
Name	ubiquitin specific peptidase 21
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	USP16
Ensembl gene	ENSG00000143258
Ensembl biotype	protein_coding
OMIM	604729
Entrez	27005

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000368002

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

ENST00000368002, ENST00000289865, ENST00000368001, ENST00000479344, ENST00000482385, ENST00000485277, ENST00000486299, ENST00000487163, ENST00000492950, ENST00000493054, ENST00000696603, ENST00001145199

RefSeq mRNA: 4 — MANE Select: NM_001014443 NM_001014443, NM_001319847, NM_001319848, NM_012475

CCDS: CCDS30920, CCDS81392

Canonical transcript exons

ENST00000368002 — 14 exons

Exon	Start	End
ENSE00001446103	161159500	161159678
ENSE00001510990	161160366	161160506
ENSE00003461622	161163555	161163619
ENSE00003469749	161165029	161165143
ENSE00003524118	161162270	161162390
ENSE00003563292	161162615	161162726
ENSE00003572416	161164835	161164942
ENSE00003618237	161164534	161164612
ENSE00003619578	161164164	161164250
ENSE00003632279	161162919	161163074
ENSE00003665938	161165357	161165723
ENSE00003709278	161162038	161162097
ENSE00003894977	161163878	161163981
ENSE00003895740	161160620	161161240

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4417 / max 75.1101, expressed in 1769 samples.

Highest expression (Bgee): uterine tube, hemisphere of cerebellum, ovary, granulocyte, cerebellar hemisphere.

Genetic regulation across tissues (GTEx eQTL / sQTL)

USP21 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 6 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

7 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.3e-04	+0.58	1:161731263:A:G
Whole Blood	eqtl	1.3e-02	+0.37	1:160447695:C:T
Vagina	eqtl	1.7e-02	-1.56	1:160303205:G:GCAA
Uterus	eqtl	2.8e-02	+0.19	1:161961377:A:G
Lung	eqtl	2.9e-02	-0.32	1:161188454:G:T
Adipose Subcutaneous	sqtl	3.3e-02	+0.40	1:161097295:C:T
Nerve Tibial	eqtl	4.7e-02	+0.13	1:160590319:CAT:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
6210	12.1183	1768
6211	0.1631	57
6209	0.1603	47

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.92	gold quality
right ovary	UBERON:0002118	93.66	gold quality
left ovary	UBERON:0002119	93.40	gold quality
granulocyte	CL:0000094	93.37	gold quality
cerebellar hemisphere	UBERON:0002245	93.26	gold quality
lower esophagus mucosa	UBERON:0035834	93.23	gold quality
cerebellar cortex	UBERON:0002129	93.13	gold quality
cortical plate	UBERON:0005343	92.95	gold quality
right lobe of thyroid gland	UBERON:0001119	92.88	gold quality
body of uterus	UBERON:0009853	92.87	gold quality
endocervix	UBERON:0000458	92.77	gold quality
ganglionic eminence	UBERON:0004023	92.73	gold quality
left lobe of thyroid gland	UBERON:0001120	92.53	gold quality
skin of abdomen	UBERON:0001416	92.40	gold quality
metanephros cortex	UBERON:0010533	91.97	gold quality
apex of heart	UBERON:0002098	91.94	gold quality
right frontal lobe	UBERON:0002810	91.92	gold quality
adenohypophysis	UBERON:0002196	91.85	gold quality
cerebellum	UBERON:0002037	91.81	gold quality
left uterine tube	UBERON:0001303	91.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.71	gold quality
skin of leg	UBERON:0001511	91.67	gold quality
ectocervix	UBERON:0012249	91.60	gold quality
lower esophagus	UBERON:0013473	91.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.58	gold quality
body of stomach	UBERON:0001161	91.56	gold quality
right coronary artery	UBERON:0001625	91.51	gold quality
thyroid gland	UBERON:0002046	91.42	gold quality
pituitary gland	UBERON:0000007	91.32	gold quality
ventricular zone	UBERON:0003053	91.18	gold quality
right adrenal gland	UBERON:0001233	91.17	gold quality
right adrenal gland cortex	UBERON:0035827	91.14	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.11	gold quality
nerve	UBERON:0001021	90.76	gold quality
tibial nerve	UBERON:0001323	90.76	gold quality
spleen	UBERON:0002106	90.74	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.69	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.66	gold quality
body of pancreas	UBERON:0001150	90.49	gold quality
mucosa of stomach	UBERON:0001199	90.47	gold quality
minor salivary gland	UBERON:0001830	90.29	gold quality
esophagus	UBERON:0001043	90.28	gold quality
left adrenal gland cortex	UBERON:0035825	90.25	gold quality
gastrocnemius	UBERON:0001388	90.17	gold quality
transverse colon	UBERON:0001157	90.13	gold quality
left adrenal gland	UBERON:0001234	90.10	gold quality
left coronary artery	UBERON:0001626	90.10	gold quality
right testis	UBERON:0004534	90.09	gold quality
ovary	UBERON:0000992	90.08	gold quality
mucosa of transverse colon	UBERON:0004991	89.99	gold quality
left testis	UBERON:0004533	89.77	gold quality
coronary artery	UBERON:0001621	89.67	gold quality
muscle of leg	UBERON:0001383	89.55	gold quality
adrenal cortex	UBERON:0001235	89.54	gold quality
anterior cingulate cortex	UBERON:0009835	89.54	gold quality
esophagus mucosa	UBERON:0002469	89.52	gold quality
popliteal artery	UBERON:0002250	89.50	gold quality
tibial artery	UBERON:0007610	89.50	gold quality
cingulate cortex	UBERON:0003027	89.49	gold quality
descending thoracic aorta	UBERON:0002345	89.47	gold quality
zone of skin	UBERON:0000014	89.45	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.45	gold quality
fundus of stomach	UBERON:0001160	89.42	gold quality
thoracic aorta	UBERON:0001515	89.40	gold quality
aorta	UBERON:0000947	89.39	gold quality
stomach	UBERON:0000945	89.36	gold quality
ascending aorta	UBERON:0001496	89.34	gold quality
amygdala	UBERON:0001876	89.32	gold quality
right lung	UBERON:0002167	89.26	gold quality
small intestine	UBERON:0002108	89.25	gold quality
caudate nucleus	UBERON:0001873	89.22	gold quality
nucleus accumbens	UBERON:0001882	89.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.98	gold quality
upper lobe of left lung	UBERON:0008952	88.90	gold quality
vagina	UBERON:0000996	88.82	gold quality
mouth mucosa	UBERON:0003729	88.82	gold quality
prefrontal cortex	UBERON:0000451	88.81	gold quality
right lobe of liver	UBERON:0001114	88.60	gold quality
rectum	UBERON:0001052	88.52	gold quality
omental fat pad	UBERON:0010414	88.48	gold quality
adrenal gland	UBERON:0002369	88.47	gold quality
right atrium auricular region	UBERON:0006631	88.47	gold quality
peritoneum	UBERON:0002358	88.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.43	gold quality
embryo	UBERON:0000922	88.36	gold quality
testis	UBERON:0000473	88.35	gold quality
neocortex	UBERON:0001950	88.28	gold quality
lymph node	UBERON:0000029	88.27	gold quality
putamen	UBERON:0001874	88.27	gold quality
oocyte	CL:0000023	88.20	gold quality
bronchial epithelial cell	CL:0002328	88.20	gold quality
spinal cord	UBERON:0002240	88.17	gold quality
frontal cortex	UBERON:0001870	88.16	gold quality
frontal lobe	UBERON:0016525	88.15	gold quality
upper lobe of lung	UBERON:0008948	87.99	gold quality
saliva-secreting gland	UBERON:0001044	87.96	gold quality
stromal cell of endometrium	CL:0002255	87.81	gold quality
secondary oocyte	CL:0000655	87.78	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.40
E-GEOD-99795	no	74.42

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	32.9
Frontal cortex	tissue	31.5
Hippocampal formation	tissue	28.4
Basal ganglia	tissue	27.6	not detected
Fallopian tube	tissue	26.8	low
Choroid plexus	tissue	24.2
Nucleus accumbens	tissue	24.1
Hippocampus	tissue	24.0	low
Periaqueductal gray	tissue	24.0
Prefrontal cortex	tissue	23.8
Cerebral cortex	tissue	23.8	low
Putamen	tissue	23.7
Somatosensory cortex	tissue	23.5
Septum	tissue	23.1
Ventral forebrain	tissue	22.8
Hypothalamus	tissue	22.7
Occipital cortex	tissue	22.7
Motor cortex	tissue	22.6
Postcentral gyrus	tissue	22.6
Corpus callosum	tissue	22.5
Temporal cortex	tissue	22.5
Entorhinal cortex	tissue	22.0
Ovary	tissue	21.9	not detected
Amygdala	tissue	21.9
Pons	tissue	21.8
Thalamus	tissue	21.6
Retrosplenial cortex	tissue	21.5
Insular cortex	tissue	21.4
Retrosplenial and cingulate cortex	tissue	21.3
Midbrain	tissue	20.9
Medulla oblongata	tissue	20.9
Olfactory bulb	tissue	20.9
Locus coeruleus	tissue	20.4
Substantia nigra	tissue	20.3
Seminal vesicle	tissue	20.2	medium
Skin 1	tissue	19.9	not detected
Superior colliculi	tissue	19.9
Cerebellum	tissue	19.5	low
Spinal cord	tissue	18.7
Thymus	tissue	17.8
Skeletal muscle	tissue	17.2	not detected
Parathyroid gland	tissue	16.9	medium
Tongue	tissue	16.9
Epididymis	tissue	16.1	low
Vagina	tissue	15.9	not detected
Salivary gland	tissue	15.5	low
Pancreas	tissue	15.4	low
Lymph node	tissue	15.1	not detected
Spleen	tissue	14.8	not detected
Tonsil	tissue	14.8	not detected
Esophagus	tissue	14.7	not detected
Pituitary gland	tissue	14.5
Thyroid gland	tissue	14.5	low
Endometrium 1	tissue	14.3	medium
Bone marrow	tissue	14.2	not detected
Cervix	tissue	13.9	low
Prostate	tissue	13.8	low
Smooth muscle	tissue	13.5	not detected
Retina	tissue	13.0
Placenta	tissue	12.9	low

Brain sub-regions (HPA Brain Atlas): detected in 292; highest nTPM — Caudate nucleus (57.5), Fusiform gyrus (48.9), Lingual gyrus (47.7), Nucleus basalis of Meynert (45.8), Inferior temporal gyrus (44.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXP3, GATA3, NOTO

miRNA regulators (miRDB)

Targeting USP21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 47 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4718	98.55	68.61	814

Functional genomics

gnomAD constraint: pLI 4.99e-05, LOEUF 0.671, missense Z 2.54 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000368002 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:161,160,641–161,162,039	284 / 281.0	1.01	no
1:161,162,040–161,163,005	87 / 162.4	0.54	no
1:161,163,006–161,163,074	40 / 29.3	1.37	no
1:161,163,555–161,165,444	173 / 268.2	0.65	no

Literature-anchored findings (GeneRIF, showing 29)

• USP21 plays an important role in the down-regulation of TNFalpha-induced NF-kappaB activation through deubiquitinating RIP1. (PMID:19910467)
• Study report that USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8. (PMID:21399617)
• Study observed a reduction in the number of A549 cells developing a primary cilium upon serum starvation when USP21 was depleted with two independent siRNA oligos. (PMID:22298430)
• Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3 (PMID:23395819)
• The protein stability of IL-33 is maintained by USP21 through deubiquitination (PMID:25197364)
• Data show that SUMOylated BANP, E5R, and Nac1 (BEN) domain 3 (BEND3) stabilizes NoRC component TTF-1-interacting protein 5 (Tip5)via association with ubiquitin specific protease 21 (USP21) debiquitinase (PMID:26100909)
• Results from computational biology identified a cancer mutation that inactivates the nuclear export signals of the human deubiquitinase USP21, and leads to the aberrant accumulation of this protein in the nucleus. (PMID:27174732)
• USP21 binds to the promoter region of IL-8 and mediates transcriptional initiation, which regulates the stem-cell like property of human renal cell carcinoma (PMID:27259257)
• Data show that ubiquitin variants (Ubvs) that bind to USP2 or USP21 contain a similar core functional epitope, or “hot spot,” consisting mainly of positions that are conserved as the wild type sequence, but also some positions that prefer mutant sequences. (PMID:27436899)
• USP21 recruits and stabilises Gli1 at the centrosome. (PMID:27621083)
• USP21 specifically regulates the Lys48-linked polyubiquitination and stability of NANOG (PMID:27956178)
• a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses. (PMID:28254948)
• USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. (PMID:28743957)
• USP21-mediated deubiquitination and stabilization of MEK2 plays a critical role in hepatocellular carcinoma development. (PMID:29706623)
• USP21 binds and deubiquitinates FOXM1 in breast cancer cells. (PMID:30865895)
• USP21 modulates Goosecoid function through deubiquitination. (PMID:31253698)
• work identifies and validates USP21 as a PDAC oncogene (PMID:31488580)
• The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer. (PMID:31956270)
• USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase-dependent manner. (PMID:33052017)
• USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B-cell lymphoma. (PMID:33389794)
• Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21. (PMID:33582217)
• Deubiquitinating Enzyme USP21 Inhibits HIV-1 Replication by Downregulating Tat Expression. (PMID:33827943)
• Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes. (PMID:34523817)
• USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer. (PMID:34825342)
• USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1. (PMID:35974001)
• USP21 accelerates the proliferation and glycolysis of esophageal cancer cells by regulating the STAT3/FOXO1 pathway. (PMID:36095935)
• Salt-like transcription factor 4 promotes laryngeal cancer progression through transcriptional activation of ubiquitin-specific protease 21 to stabilize Yin Yang 1. (PMID:36285444)
• c-JUN-induced upregulation of LINC00174 contributes to colorectal cancer proliferation and invasion through accelerating USP21 expression. (PMID:37434557)
• Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling. (PMID:37964466)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp21	ENSDARG00000094280
mus_musculus	Usp21	ENSMUSG00000053483
rattus_norvegicus	Usp21	ENSRNOG00000038347
drosophila_melanogaster	Usp2	FBGN0031187

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832), USP19 (ENSG00000172046), USP18 (ENSG00000184979), USP7 (ENSG00000187555), USP17L2 (ENSG00000223443), USP17L15 (ENSG00000223569), USP17L3 (ENSG00000225327), USP17L7 (ENSG00000226430), USP17L5 (ENSG00000227140), USP17L12 (ENSG00000227551), USP17L30 (ENSG00000228856), USP17L26 (ENSG00000229579), USP17L25 (ENSG00000230430), USP17L1 (ENSG00000230549), USP17L28 (ENSG00000231051), USP17L10 (ENSG00000231396), USP17L29 (ENSG00000231637), USP17L24 (ENSG00000232264), USP17L13 (ENSG00000232399), USP17L11 (ENSG00000233136), USP17L27 (ENSG00000235780)

+11 more (showing top 60).

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1353665) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 16 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased leukocyte cell number	1
increased neutrophil cell number	1
enlarged spleen	1
abnormal embryonic tissue morphology	1
abnormal pluripotent precursor cell morphology	1
increased spleen weight	1
increased macrophage cell number	1
decreased mean corpuscular hemoglobin	1
decreased blood urea nitrogen level	1
increased circulating interferon-alpha level	1
increased circulating interferon-beta level	1
abnormal interferon level	1
increased splenocyte number	1
decreased circulating fructosamine level	1
decreased susceptibility to Riboviria infection	1
decreased susceptibility to Riboviria infection induced morbidity/mortality	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
Aspergillus flavus NRRL3357	B8NSV5	99.9%	Diamond
Aspergillus oryzae RIB40	Q2UUG8	99.9%	Diamond
Saccharomyces cerevisiae RM11-1a	B3LGK1	99.8%	Diamond
Saccharomyces cerevisiae S288C	P32571	99.8%	Diamond
Saccharomyces cerevisiae YJM789	A6ZY34	99.6%	Diamond
Pongo abelii	Q5R5Z6	98.8%	Diamond
Bos taurus	Q2HJE4	97.4%	Diamond
Arabidopsis thaliana	Q93Y01	93.3%	Diamond
Macaca fascicularis	Q4R6D3	90.0%	Diamond
Xenopus tropicalis	F6Z5C0	85.6%	Diamond
Canis lupus familiaris	Q01988	79.3%	Diamond
Gallus gallus	O57429	77.8%	Diamond
Oryza sativa Japonica Group	Q0E2F9	53.1%	Diamond
Eremothecium gossypii ATCC 10895	Q754R5	51.9%	Diamond
Vanderwaltozyma polyspora DSM 70294	A7TGY3	51.4%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q9HFS7	50.0%	Diamond
Schizosaccharomyces pombe 972h-	O60079	48.1%	Diamond
Nakaseomyces glabratus CBS 138	Q6FQF0	48.0%	Diamond
Caenorhabditis elegans	Q8WT44	44.1%	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
NIT1	protein-coding	4817
UFC1	protein-coding	51506
DEDD	protein-coding	9191
PPOX	protein-coding	5498
B4GALT3	protein-coding	8703
NDUFS2	protein-coding	4720
ADAMTS4	protein-coding	9507
FCER1G	protein-coding	2207
APOA2	protein-coding	336

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 21 — Q9UK80 (reviewed: Q9UK80)

Alternative names: Deubiquitinating enzyme 21, Ubiquitin thioesterase 21, Ubiquitin-specific-processing protease 21

All UniProt accessions (6): A0A1W2PQ32, A0A1W2PRX0, A0A8Q3SIU3, Q9UK80, V9GY36, V9GYJ6

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A releaves the repression of di- and trimethylation of histone H3 at ‘Lys-4’, resulting in regulation of transcriptional initiation. Regulates gene expression via histone H2A deubiquitination. Deubiquitinates BAZ2A/TIP5 leading to its stabilization. Also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates. Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination.

Subunit / interactions. Interacts with BEND3.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in heart, pancreas and skeletal muscle. Also expressed in brain, placenta, liver and kidney, and at very low level in lung.

Similarity. Belongs to the peptidase C19 family. USP21 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UK80-1	1	yes
Q9UK80-2	2
Q9UK80-3	3

RefSeq proteins (4): NP_001014443, NP_001306776, NP_001306777, NP_036607 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443

Enzyme classification (BRENDA)

• EC 3.4.19.12 — ubiquitinyl hydrolase 1 (BRENDA: 30 organisms, 328 substrates, 173 inhibitors, 70 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
UBIQUITIN-7-AMIDO-4-METHYLCOUMARIN	—	7
DABCYL-FKKKGGGDVKE-EDANS	0.0142–0.0616	6
UBIQUITIN 7-AMIDO-4-METHYLCOUMARIN	—	5
UBIQUITIN ETHYL ESTER	0.0006–0.03	5
DABCYL-FRLKGGAPIKGV-EDANS	0.0048–0.0217	3
UBIQUITIN-W-G75A	0.0001–0.0004	2
UBIQUITIN-W-G76A	0.0011–0.002	2
UBIQUITIN-W-H68A	0.0005	2
UBIQUITIN-W-I44A	0.0003–0.0004	2
UBIQUITIN-W-K11A	0.0011–0.0023	2
UBIQUITIN-W-K48A	0.0003–0.0007	2
UBIQUITIN-W-K63A	0.0004–0.0008	2
UBIQUITIN-W-K6A	0.0009–0.0014	2
UBIQUITIN-W-L71A	0.008–0.0198	2
UBIQUITIN-W-L73A	0.0058–0.0104	2

UniProt features (53 total): helix 15, strand 14, binding site 4, splice variant 3, sequence variant 3, sequence conflict 3, compositionally biased region 3, active site 2, chain 1, domain 1, mutagenesis site 1, region of interest 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
3I3T	Crystal structure of covalent ubiquitin-USP21 complex	X-RAY DIFFRACTION	2.59
2Y5B	Structure of USP21 in complex with linear diubiquitin-aldehyde	X-RAY DIFFRACTION	2.7
3MTN	Usp21 in complex with a ubiquitin-based, USP21-specific inhibitor	X-RAY DIFFRACTION	2.7
9NY4	USP21 bound to H2AK119ub nucleosome	ELECTRON MICROSCOPY	2.98

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK80-F1	70.70	0.52

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; plasma membrane

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
221	nucleophile
518	proton acceptor

Ligand- & substrate-binding residues (4)

Position	Role
387	Zn(2+)
437	Zn(2+)
440	Zn(2+)
384	Zn(2+)

Mutagenesis-validated functional residues (1)

Position	Phenotype
221	abolishes ubiquitin thioesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-5357905	Regulation of TNFR1 signaling	curated
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway	curated
R-HSA-5357786	TNFR1-induced proapoptotic signaling	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-73887	Death Receptor Signaling	—
R-HSA-5688426	Deubiquitination	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-162582	Signal Transduction	—
R-HSA-75893	TNF signaling	—

MSigDB gene sets: 289 (showing top): GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_PROTEIN_HOMOTETRAMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, PATIL_LIVER_CANCER, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_ORGANELLE_FISSION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (5): proteolysis (GO:0006508), protein deubiquitination (GO:0016579), transcription initiation-coupled chromatin remodeling (GO:0045815), chromatin organization (GO:0006325), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), cysteine-type deubiquitinase activity (GO:0004843), cysteine-type peptidase activity (GO:0008234), deNEDDylase activity (GO:0019784), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nucleus (GO:0005634)

Reactome top-level categories

6 top-level categories:

Category	Pathways
TNF signaling	3
Deubiquitination	1
Post-translational protein modification	1
Metabolism of proteins	1
Signal Transduction	1
Death Receptor Signaling	1

GO top-level categories

25 GO namespaces:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of gene expression, epigenetic	1
cellular component organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
peptidase activity	1
ubiquitin-like protein peptidase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
protein deubiquitination	BP	direct assay
cytosol	CC	direct assay
nucleoplasm	CC	direct assay
cysteine-type deubiquitinase activity	MF	direct assay
cysteine-type peptidase activity	MF	mutant phenotype
deNEDDylase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 840 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP21	NEDD8	Q15843	692
USP21	RIPK1	Q13546	663
USP21	MYSM1	Q5VVJ2	572
USP21	H2AC20	Q16777	569
USP21	H2AC19	P20670	569
USP21	OTUB1	Q96FW1	556
USP21	ZUP1	Q96AP4	520
USP21	UCHL3	P15374	496
USP21	CYLD	Q9NQC7	487
USP21	USP28	Q96RU2	486
USP21	OTULIN	Q96BN8	457
USP21	ARL16	Q0P5N6	448
USP21	SENP8	Q96LD8	447
USP21	RNF125	Q96EQ8	446
USP21	SUMO1	P55856	439

IntAct

Human interaction partners of USP21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 56 partners by confidence:

Partner	Interaction type	MIscore	Records
UCHL1	physical association	0.670	3
ADAMTSL4	physical association	0.560	3
CPSF6	physical association	0.560	3
EFEMP2	physical association	0.560	3
HOXC10	physical association	0.560	3
KCTD9	physical association	0.560	3
KRT40	physical association	0.560	3
ANKRD28	association	0.350	1
AFDN	physical association	0.000	1
AGAP1	physical association	0.000	1
ANKRD34A	physical association	0.000	1
CBY1	physical association	0.000	1
CDC25B	physical association	0.000	1
CDK16	physical association	0.000	1
DCLK1	physical association	0.000	1
DENND1A	physical association	0.000	1
DENND4C	physical association	0.000	1
DEPDC1B	physical association	0.000	1
EIF4E2	physical association	0.000	1
EXOSC10	physical association	0.000	1
FAM110A	physical association	0.000	1
FAM110B	physical association	0.000	1
FAM53C	physical association	0.000	1
GAB2	physical association	0.000	1
GIGYF1	physical association	0.000	1
HDAC4	physical association	0.000	1
KCTD3	physical association	0.000	1
KIF13B	physical association	0.000	1
KIF1C	physical association	0.000	1
KSR1	physical association	0.000	1

BioGRID (230 interactions; top human partners by supporting records): NANOG (Affinity Capture-Western; 13 records), UBC (Biochemical Activity; 12 records), AURKA (Biochemical Activity; 5 records), FOXM1 (Affinity Capture-Western; 4 records), GATA3 (Affinity Capture-Western; 4 records), YOD1 (Affinity Capture-Western; 4 records), DDX58 (Affinity Capture-Western; 3 records), FOXD1 (Affinity Capture-Western; 3 records), KCTD6 (Two-hybrid; 3 records), MARK2 (Affinity Capture-MS; 3 records), RIPK1 (Biochemical Activity; 3 records), BEND3 (Affinity Capture-Western; 2 records), BRCA2 (Affinity Capture-Western; 2 records), CUL3 (Affinity Capture-Western; 2 records), FOXO3 (Affinity Capture-Western; 2 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
MAPK14	“up-regulates activity”	USP21	phosphorylation
USP21	“down-regulates activity”	STING1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 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
CDC42 GTPase cycle	6	12.1×	2e-03
RHO GTPase cycle	6	10.0×	2e-03

Disease & clinical

Genetic variants

Variant evidence for USP21: 90 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 1,185):

Position(s)	Effect	Δscore	Sites
1:161162260	acceptor_gain	1.0000
1:161162268	acceptor_loss	1.0000
1:161162391	donor_loss	1.0000	2
1:161162910–161162911	acceptor_gain	1.0000	2
1:161162914	acceptor_gain	1.0000
1:161162917–161162918	acceptor_loss	1.0000	6
1:161163070	donor_gain	1.0000
1:161163542	acceptor_gain	1.0000
1:161159679–161159680	donor_loss	0.9900	5
1:161160618–161160619	acceptor_loss	0.9900	6

AlphaMissense

1,371 missense substitutions predicted likely pathogenic (of 3,588 scored), across 309 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
D301	8	1.000	1.000
D534	8	1.000	1.000
N216	8	0.999	1.000
H510	8	0.999	1.000
H518	8	0.999	1.000
N219	8	0.996	1.000
F466	8	0.995	1.000
H462	8	0.993	0.998
F397	8	0.992	0.999
F554	8	0.990	0.999
H314	8	0.988	0.995
F374	8	0.988	0.999
N224	8	0.985	1.000
F294	8	0.981	0.999
F305	8	0.980	0.999
D399	8	0.980	0.990
F283	8	0.976	1.000
S368	8	0.974	1.000
S380	8	0.973	0.999
F287	8	0.972	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.39e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	8.28e-05
Colon Adenocarcinoma (validation)	unfavorable	0.000345

Disease associations

OMIM: gene MIM:604729 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2157852 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C19: Ubiquitin-specific protease

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
BAY-805	Inhibition	8.22	pIC50

Binding affinities (BindingDB)

11 measured of 24 human assays (28 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5286335	IC50	11 nM
CHEMBL5268828	IC50	12 nM
CHEMBL5277351	IC50	28 nM
CHEMBL5267932	IC50	32 nM
CHEMBL5271965	IC50	36 nM
CHEMBL5279700	IC50	65 nM
CHEMBL5280287	IC50	72 nM
CHEMBL5266176	IC50	100 nM
CHEMBL5279102	IC50	7610 nM
CHEMBL5284472	IC50	21500 nM
CHEMBL5269090	IC50	25000 nM

ChEMBL bioactivities

30 potent at pChembl≥5 of 36 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.78	EC50	0.0166	nM	CHEMBL5279102
10.02	EC50	0.095	nM	CHEMBL5279102
8.70	IC50	2	nM	CHEMBL5279102
8.66	Kd	2.2	nM	CHEMBL5279102
8.24	Kd	5.8	nM	CHEMBL5286335
8.22	IC50	6	nM	CHEMBL5279102
8.10	IC50	8	nM	CHEMBL5268828
8.10	Kd	7.87	nM	CHEMBL5273043
7.96	IC50	11	nM	CHEMBL5286335
7.92	IC50	12	nM	CHEMBL5268828
7.75	IC50	18	nM	CHEMBL5286335
7.55	IC50	28	nM	CHEMBL5277351
7.50	IC50	32	nM	CHEMBL5277351
7.50	IC50	32	nM	CHEMBL5275560
7.50	IC50	32	nM	CHEMBL5267932
7.44	IC50	36	nM	CHEMBL5271965
7.35	IC50	45	nM	CHEMBL5271965
7.35	IC50	45	nM	CHEMBL5266176
7.19	IC50	65	nM	CHEMBL5279700
7.14	IC50	73	nM	CHEMBL5275560
7.14	IC50	72	nM	CHEMBL5280287
7.14	IC50	72	nM	CHEMBL5274527
7.13	IC50	74	nM	CHEMBL5275910
7.08	IC50	84	nM	CHEMBL5267932
7.00	IC50	100	nM	CHEMBL5266176
6.92	IC50	119	nM	CHEMBL5274527
6.66	IC50	221	nM	CHEMBL5278034
6.12	IC50	754	nM	CHEMBL5278034
5.23	IC50	5870	nM	CHEMBL5269090
5.15	IC50	7140	nM	CHEMBL5269090

PubChem BioAssay actives

30 with measured affinity, of 108 total; 15 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
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947440: Inhibition of full-length human USP21 transfected in human HEK293T cells co-transfected with NF-kappaB reporter firefly luciferase plasmid assessed as NF-kappaB activation and measured after 20 hrs by dual-luciferase reporter gene assay	ec50	<0.0001	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947414: Binding affinity to recombinant human N-terminal His6-tagged USP21 (209 to 563 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by SPR analysis	kd	0.0058	uM
N-[1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclopentanecarboxamide	1947414: Binding affinity to recombinant human N-terminal His6-tagged USP21 (209 to 563 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by SPR analysis	kd	0.0079	uM
N-[(1R)-2-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-cyclopentyl-2-oxoethyl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0080	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-ethylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0280	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(difluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0320	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0320	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0360	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-hydroxy-3-methyl-1-oxobutan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0450	uM
N-[(2R)-1-[[2-[(4-cyanophenyl)methyl]-4-methyl-1,3-thiazol-5-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0650	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-4-methyl-1,3-thiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0720	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0720	uM
N-[(2R)-3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0740	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclohexanecarboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.2210	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclopentanecarboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	5.8700	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
moringin	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cannabidiol	increases expression	1
Doxorubicin	decreases expression	1
Gallic Acid	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression, increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2163014	Binding	Inhibition of HIs6-tagged USP21 by Ub-CHOP reporter assay	Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. — *ACS Med Chem Lett*

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 telomerase immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3KV	N/Tert-1 USP21	Telomerase immortalized cell line	Male
CVCL_D6BP	HyCyte Hep-G2 KO-hUSP21	Cancer cell line	Male
CVCL_D9VJ	Ubigene HEK293 USP21 KO	Transformed cell line	Female
CVCL_E2NJ	HAP1 USP21 (-) 3	Cancer cell line	Male
CVCL_E2NK	HAP1 USP21 (-) 4	Cancer cell line	Male
CVCL_E2NL	HAP1 USP21 (-) 5	Cancer cell line	Male
CVCL_TW74	HAP1 USP21 (-) 1	Cancer cell line	Male
CVCL_TW75	HAP1 USP21 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for USP21 across ~30M SureChEMBL compounds — explore on Sugi Predict.