USP16

Summary

USP16 (ubiquitin specific peptidase 16, HGNC:12614) is a protein-coding gene on chromosome 21q21.3, encoding Ubiquitin carboxyl-terminal hydrolase 16 (Q9Y5T5). Specifically deubiquitinates ‘Lys-120’ of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator.

This gene encodes a deubiquitinating enzyme that is phosphorylated at the onset of mitosis and then dephosphorylated at the metaphase/anaphase transition. It can deubiquitinate H2A, one of two major ubiquitinated proteins of chromatin, in vitro and a mutant form of the protein was shown to block cell division. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 10600 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 122 total
• Druggable target: yes
• MANE Select transcript: NM_006447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12614
Approved symbol	USP16
Name	ubiquitin specific peptidase 16
Location	21q21.3
Locus type	gene with protein product
Status	Approved
Aliases	Ubp-M
Ensembl gene	ENSG00000156256
Ensembl biotype	protein_coding
OMIM	604735
Entrez	10600

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 34 protein_coding, 2 retained_intron

ENST00000334352, ENST00000399973, ENST00000399975, ENST00000399976, ENST00000474835, ENST00000485067, ENST00000885881, ENST00000885882, ENST00000885883, ENST00000885884, ENST00000885885, ENST00000885886, ENST00000885887, ENST00000885888, ENST00000885889, ENST00000885890, ENST00000885891, ENST00000885892, ENST00000885893, ENST00000885894, ENST00000928000, ENST00000928001, ENST00000928002, ENST00000928003, ENST00000928004, ENST00000928005, ENST00000952481, ENST00000952482, ENST00000952483, ENST00000952484, ENST00000952485, ENST00000952486, ENST00000952487, ENST00000952488, ENST00000952489, ENST00000952490

RefSeq mRNA: 3 — MANE Select: NM_006447 NM_001001992, NM_001032410, NM_006447

CCDS: CCDS13583, CCDS42912

Canonical transcript exons

ENST00000399976 — 18 exons

Exon	Start	End
ENSE00001025441	29042472	29042528
ENSE00001025450	29043423	29043599
ENSE00003458546	29046667	29047321
ENSE00003459896	29039026	29039156
ENSE00003460845	29053802	29053958
ENSE00003463886	29042013	29042104
ENSE00003496277	29036271	29036374
ENSE00003514567	29050092	29050178
ENSE00003520051	29037276	29037463
ENSE00003525236	29038335	29038430
ENSE00003535264	29054066	29054488
ENSE00003539453	29048761	29048855
ENSE00003551154	29040609	29040687
ENSE00003551291	29039481	29039568
ENSE00003603870	29034837	29034940
ENSE00003626880	29027873	29027974
ENSE00003638792	29030595	29030773
ENSE00003842231	29024668	29024777

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.5452 / max 1147.3589, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188716	35.2403	1808
188715	1.2492	759
188718	0.0371	10
188719	0.0187	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	96.76	gold quality
sperm	CL:0000019	95.92	gold quality
epithelium of nasopharynx	UBERON:0001951	95.90	gold quality
pylorus	UBERON:0001166	95.45	gold quality
calcaneal tendon	UBERON:0003701	95.45	gold quality
secondary oocyte	CL:0000655	95.31	gold quality
tendon	UBERON:0000043	94.92	gold quality
colonic epithelium	UBERON:0000397	94.85	gold quality
male germ cell	CL:0000015	94.00	gold quality
tendon of biceps brachii	UBERON:0008188	93.94	gold quality
parietal pleura	UBERON:0002400	93.89	gold quality
cardia of stomach	UBERON:0001162	93.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.39	gold quality
pleura	UBERON:0000977	93.30	gold quality
medial globus pallidus	UBERON:0002477	93.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.08	gold quality
rectum	UBERON:0001052	92.90	gold quality
deltoid	UBERON:0001476	92.90	gold quality
tibialis anterior	UBERON:0001385	92.86	gold quality
corpus callosum	UBERON:0002336	92.72	gold quality
globus pallidus	UBERON:0001875	92.67	gold quality
amniotic fluid	UBERON:0000173	92.58	gold quality
inferior vagus X ganglion	UBERON:0005363	92.51	gold quality
islet of Langerhans	UBERON:0000006	92.42	gold quality
tonsil	UBERON:0002372	92.42	gold quality
visceral pleura	UBERON:0002401	92.40	gold quality
nipple	UBERON:0002030	92.37	gold quality
upper leg skin	UBERON:0004262	92.16	gold quality
urethra	UBERON:0000057	92.14	gold quality
tibia	UBERON:0000979	92.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.93
E-HCAD-31	no	2.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting USP16, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-493-5P	99.96	72.47	2382
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-205-3P	99.92	69.92	3165
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716

Literature-anchored findings (GeneRIF, showing 16)

• Study reports the solution structure of the BUZ domain of Ubp-M, a ubiquitin-specific protease, and its interaction with ubiquitin; the Ubp-M BUZ domain features three zinc-binding sites consisting of 12 residues. (PMID:17512543)
• knockdown of Ubp-M in HeLa cells results in slow cell growth rates owing to defects in the mitotic phase of the cell cycle (PMID:17914355)
• a new cryptic USP16-RUNX1 fusion in chronic myelomonocytic leukemia (PMID:18925961)
• S552P disrupts the interaction between Ubp-M and nuclear export protein CRM1, increasing Ubp-M nuclear retention as cells progress into M phase, revealing a critical function for Ubp-M S552P. (PMID:24013421)
• in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down’s syndrome fibroblasts (PMID:24025767)
• Data show that histone H2A deubiquitinase USP16 interacts with E3 ubiquitin-protein ligase HERC2, negatively regulates DNA damage-induced ubiquitin foci formation, and is required for termination of the ubiquitin signal. (PMID:25305019)
• The data unveil a unique mechanism by which Usp16 promotes the localization and maintenance of Plk1 on the kinetochores for proper chromosome alignment. (PMID:26323689)
• USP16 and TTC3 were dysregulated in all affected human cells and two mouse models of Down syndrome. (PMID:27586445)
• USP16 was frequently downregulated. (PMID:27633997)
• data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. (PMID:31135381)
• USP16 gene expression is tightly regulated at transcription level. (PMID:31888715)
• USP16 counteracts mono-ubiquitination of RPS27a and promotes maturation of the 40S ribosomal subunit. (PMID:32129764)
• USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination. (PMID:32999190)
• USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc. (PMID:33546726)
• LncRNA MNX1-AS1 sustains inactivation of Hippo pathway through a positive feedback loop with USP16/IGF2BP3 axis in gallbladder cancer. (PMID:35953000)
• O-GlcNAcylation stimulates the deubiquitination activity of USP16 and regulates cell cycle progression. (PMID:38462164)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp16	ENSDARG00000060633
mus_musculus	Usp16	ENSMUSG00000025616
rattus_norvegicus	Usp16	ENSRNOG00000001598

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), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 16 — Q9Y5T5 (reviewed: Q9Y5T5)

Alternative names: Deubiquitinating enzyme 16, Ubiquitin thioesterase 16, Ubiquitin-processing protease UBP-M, Ubiquitin-specific-processing protease 16

All UniProt accessions (2): Q9Y5T5, H9KVB6

UniProt curated annotations — full annotation on UniProt →

Function. Specifically deubiquitinates ‘Lys-120’ of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A is a prerequisite for subsequent phosphorylation at ‘Ser-11’ of histone H3 (H3S10ph), and is required for chromosome segregation when cells enter into mitosis. In resting B- and T-lymphocytes, phosphorylation by AURKB leads to enhance its activity, thereby maintaining transcription in resting lymphocytes. Regulates Hox gene expression via histone H2A deubiquitination. Prefers nucleosomal substrates. Does not deubiquitinate histone H2B. Also deubiquitinates non-histone proteins, such as ribosomal protein RPS27A: deubiquitination of monoubiquitinated RPS27A promotes maturation of the 40S ribosomal subunit. Also mediates deubiquitination of tektin proteins (TEKT1, TEKT2, TEK3, TEKT4 and TEKT5), promoting their stability.

Subunit / interactions. Homotetramer. Associates with late pre-40S ribosomes. Interacts with CEP78; promoting deubiquitination of tektins.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Present in all the tissues examined including fetal brain, lung, liver, kidney, and adult heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Phosphorylated at the onset of mitosis and dephosphorylated during the metaphase/anaphase transition. Phosphorylation by AURKB enhances the deubiquitinase activity.

Disease relevance. A chromosomal aberration involving USP16 is a cause of Chronic myelomonocytic leukemia. Inversion inv(21) (q21;q22) with RUNX1/AML1.

Domain organisation. The UBP-type zinc finger binds 3 zinc ions that form a pair of cross-braced ring fingers encapsulated within a third zinc finger in the primary structure. It recognizes the C-terminal tail of free ubiquitin.

Miscellaneous. USP16 may contribute to somatic stem cell defects observed in Down syndrome. USP16 is triplicated in Down syndrome and its overexpression may contribute to proliferation defects in stem cells. Reduction of USP16 levels results in increased proliferation capacity of Down syndrome fibroblasts.

Similarity. Belongs to the peptidase C19 family. USP16 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y5T5-1	1	yes
Q9Y5T5-2	2
Q9Y5T5-3	3
Q9Y5T5-4	4
Q9Y5T5-5	5

RefSeq proteins (3): NP_001001992, NP_001027582, NP_006438* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR030849	UBP16	Family
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050164	Peptidase_C19	Family

Pfam: PF00443, PF02148

UniProt features (83 total): strand 23, helix 15, binding site 12, modified residue 5, sequence conflict 5, compositionally biased region 5, splice variant 4, turn 4, active site 2, region of interest 2, chain 1, domain 1, zinc finger region 1, cross-link 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9YCW	X-RAY DIFFRACTION	1.8
8WG5	ELECTRON MICROSCOPY	3.05
2I50	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5T5-F1	66.74	0.27

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): 205 (nucleophile); 758 (proton acceptor)

Ligand- & substrate-binding residues (12): 24; 26; 48; 51; 74; 77; 82; 90; 94; 103; 116; 119

Post-translational modifications (6): 189, 415, 531, 552, 554, 140

Mutagenesis-validated functional residues (1):

Position	Phenotype
205	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 172 (showing top): GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, 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, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, TGCTGAY_UNKNOWN

GO Biological Process (17): regulation of transcription by RNA polymerase II (GO:0006357), proteolysis (GO:0006508), DNA damage response (GO:0006974), protein deubiquitination (GO:0016579), monoubiquitinated protein deubiquitination (GO:0035520), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of translational elongation (GO:0045901), positive regulation of transcription by RNA polymerase II (GO:0045944), protein homotetramerization (GO:0051289), cell division (GO:0051301), regulation of cell cycle (GO:0051726), positive regulation of ribosome biogenesis (GO:0090070), mitotic nuclear division (GO:0140014), mitotic cell cycle (GO:0000278), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), regulation of gene expression (GO:0010468)

GO Molecular Function (13): transcription coactivator activity (GO:0003713), cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), histone binding (GO:0042393), ribosomal small subunit binding (GO:0043024), ubiquitin binding (GO:0043130), histone H2A deubiquitinase activity (GO:0140950), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
cell cycle	2
cysteine-type peptidase activity	2
cellular anatomical structure	2
protein metabolic process	1
cellular response to stress	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
protein deubiquitination	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
translational elongation	1
regulation of translational elongation	1
positive regulation of translation	1
regulation of transcription by RNA polymerase II	1
protein homooligomerization	1
protein tetramerization	1
cellular process	1
regulation of cellular process	1
ribosome biogenesis	1
positive regulation of cellular component biogenesis	1
regulation of ribosome biogenesis	1
mitotic cell cycle	1
nuclear division	1
mitotic cell cycle process	1
mitotic nuclear division	1
cellular component organization	1
chromatin organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
transcription coregulator activity	1
endopeptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
protein binding	1
ribosome binding	1
ubiquitin-like protein binding	1
histone deubiquitinase activity	1

Protein interactions and networks

STRING

890 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP16	FGD6	Q6ZV73	718
USP16	H2AC19	P20670	708
USP16	SLC7A5	Q01650	648
USP16	ASNS	P08184	640
USP16	MYSM1	Q5VVJ2	630
USP16	H2BC21	Q16778	626
USP16	H2AC20	Q16777	619
USP16	TRIB3	Q96RU7	590
USP16	SLC3A2	P08195	549
USP16	SGO1	Q5FBB7	543
USP16	USP5	P45974	508
USP16	HASPIN	Q8TF76	493
USP16	ZUP1	Q96AP4	470
USP16	RWDD2B	P57060	463
USP16	USP39	Q53GS9	455

IntAct

26 interactions, top by confidence:

A	B	Type	Score
USP16	HERC2	psi-mi:“MI:0914”(association)	0.530
ALPG	ALPP	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
USP16	H1-5	psi-mi:“MI:0915”(physical association)	0.400
USP16	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
HSCB	USP16	psi-mi:“MI:0915”(physical association)	0.370
USP16		psi-mi:“MI:0914”(association)	0.350
BYSL	RPS3A	psi-mi:“MI:0914”(association)	0.350
RACK1	RPS3A	psi-mi:“MI:0914”(association)	0.350
RPS11	SCAMP1	psi-mi:“MI:0914”(association)	0.350
RPS16	MCRIP1	psi-mi:“MI:0914”(association)	0.350
TSR1	VWA8	psi-mi:“MI:0914”(association)	0.350
G0S2	OIP5	psi-mi:“MI:0914”(association)	0.350
APOM	CT45A8	psi-mi:“MI:0914”(association)	0.350
ALPG	POTEF	psi-mi:“MI:0914”(association)	0.350
SOST	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
PPL	ECI2	psi-mi:“MI:0914”(association)	0.350
H1-1	POLRMT	psi-mi:“MI:0914”(association)	0.350
RPS19	ZNF316	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
BUD13	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
PPIL4	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
FOS	USP16	psi-mi:“MI:0915”(physical association)	0.000
USP16	PAX6	psi-mi:“MI:0915”(physical association)	0.000
USP16	XRN2	psi-mi:“MI:0915”(physical association)	0.000
USP16	SATB1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (135): USP16 (Affinity Capture-Western), HERC2 (Affinity Capture-Western), RNF8 (Affinity Capture-Western), USP16 (Affinity Capture-Western), USP16 (Affinity Capture-Western), PLK1 (Affinity Capture-Western), USP16 (Reconstituted Complex), USP16 (Biochemical Activity), USP16 (Biochemical Activity), USP16 (Affinity Capture-MS), H2AFZ (Biochemical Activity), HIST2H2AC (Biochemical Activity), USP16 (Affinity Capture-MS), USP16 (Affinity Capture-MS), NEURL4 (Affinity Capture-MS)

ESM2 similar proteins: A0JM59, A2BGT0, A5PJS6, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, D2HBJ8, E1C213, E7F6T8, E9QG68, O88974, P52479, Q0V9G5, Q14694, Q15047, Q1RMU2, Q28CN3, Q2KJ09, Q2NL57, Q3KR59, Q5R5Z6, Q5RED8, Q5REG5, Q5XGZ2, Q5ZJN4, Q66H62, Q6NTR6, Q6P549, Q70CQ3, Q70CQ4, Q70EK9, Q7ZUM8, Q7ZXR7, Q80TQ2, Q8BW70, Q8C0R0, Q8C2S0

Diamond homologs: A1CIL1, A1CW53, A2Q9N1, A2XDG4, A3AF13, A4FUN7, A5D9H7, A5WWB0, A6QR55, B0Y4P5, B2GUZ1, B8NSV5, C0HB46, D0RB01, E1C213, E2RK09, E7F6T8, F1M625, F1N5V1, F1SRY5, F6Z5C0, M9PD06, O24454, O74442, O75317, O94782, O94966, P34547, P35123, P38187, P39967, P40818, P43593, P50102, P51784, P62068, P62069, Q01988, Q0CT11, Q0E2F9

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	USP16	phosphorylation
USP16	“down-regulates activity”	“Histone H2A”	deubiquitination
TTK	“down-regulates quantity by destabilization”	USP16	phosphorylation
PLK1	“up-regulates activity”	USP16	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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
Eukaryotic Translation Initiation	5	46.8×	2e-06
Cap-dependent Translation Initiation	5	46.8×	2e-06
SARS-CoV-1 modulates host translation machinery	5	46.8×	2e-06
Eukaryotic Translation Elongation	5	42.2×	2e-06
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	41.2×	2e-06
Nonsense-Mediated Decay (NMD)	5	35.3×	4e-06
SARS-CoV-2 modulates host translation machinery	5	33.9×	5e-06
Influenza Viral RNA Transcription and Replication	5	32.6×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	7	38.1×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2821 predictions. Top by Δscore:

Variant	Effect	Δscore
21:29027868:TCTA:T	acceptor_loss	1.0000
21:29027870:TA:T	acceptor_loss	1.0000
21:29027871:A:AG	acceptor_gain	1.0000
21:29027872:G:GG	acceptor_gain	1.0000
21:29027872:GATT:G	acceptor_gain	1.0000
21:29027970:TTTAG:T	donor_loss	1.0000
21:29027971:T:G	donor_gain	1.0000
21:29027971:TTAG:T	donor_loss	1.0000
21:29027972:TAG:T	donor_loss	1.0000
21:29027973:AGGTA:A	donor_loss	1.0000
21:29027974:GGTAT:G	donor_loss	1.0000
21:29027975:G:GA	donor_loss	1.0000
21:29027976:T:G	donor_loss	1.0000
21:29030590:A:AG	acceptor_gain	1.0000
21:29030593:A:AG	acceptor_gain	1.0000
21:29030593:A:T	acceptor_loss	1.0000
21:29030594:G:GA	acceptor_gain	1.0000
21:29030594:GA:G	acceptor_gain	1.0000
21:29030594:GAAC:G	acceptor_gain	1.0000
21:29030771:CAGGT:C	donor_loss	1.0000
21:29030774:G:GC	donor_loss	1.0000
21:29030775:T:G	donor_loss	1.0000
21:29034836:GGGCT:G	acceptor_gain	1.0000
21:29036261:T:TA	acceptor_gain	1.0000
21:29036371:CCAGG:C	donor_loss	1.0000
21:29036372:CAGGT:C	donor_loss	1.0000
21:29036373:AG:A	donor_loss	1.0000
21:29036374:GG:G	donor_loss	1.0000
21:29036375:GT:G	donor_loss	1.0000
21:29036376:T:A	donor_loss	1.0000

AlphaMissense

5528 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:29037442:T:G	C205W	1.000
21:29037443:T:C	F206L	1.000
21:29037445:C:A	F206L	1.000
21:29037445:C:G	F206L	1.000
21:29039513:A:C	D299A	1.000
21:29039513:A:T	D299V	1.000
21:29039515:A:C	S300R	1.000
21:29039517:C:A	S300R	1.000
21:29039517:C:G	S300R	1.000
21:29039525:T:C	L303P	1.000
21:29048847:T:C	F700L	1.000
21:29048849:T:A	F700L	1.000
21:29048849:T:G	F700L	1.000
21:29053878:G:A	G757E	1.000
21:29054092:T:A	W793R	1.000
21:29054092:T:C	W793R	1.000
21:29037427:T:A	N200K	0.999
21:29037427:T:G	N200K	0.999
21:29037432:G:A	G202E	0.999
21:29037436:C:A	N203K	0.999
21:29037436:C:G	N203K	0.999
21:29037440:T:C	C205R	0.999
21:29037441:G:A	C205Y	0.999
21:29037451:T:A	N208K	0.999
21:29037451:T:G	N208K	0.999
21:29037452:G:C	A209P	0.999
21:29039491:T:C	F292L	0.999
21:29039492:T:C	F292S	0.999
21:29039493:T:A	F292L	0.999
21:29039493:T:G	F292L	0.999

dbSNP variants (sampled 300 via entrez): RS1000051558 (21:29048325 T>C), RS1000059833 (21:29046013 G>A), RS1000154633 (21:29054613 T>A), RS1000179744 (21:29049304 C>G), RS1000208598 (21:29042067 A>C), RS1000278419 (21:29045751 G>A,T), RS1000312932 (21:29048572 A>G), RS1000493625 (21:29043721 A>G), RS1000512108 (21:29043984 G>A), RS1000773616 (21:29050829 C>T), RS1000784855 (21:29036372 C>T), RS1000836270 (21:29052292 G>C), RS1000912577 (21:29030061 A>C), RS1000957271 (21:29029594 G>A), RS1001051130 (21:29049824 G>A)

Disease associations

OMIM: gene MIM:604735 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630865 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.89	Kd	1300	nM	CHEMBL5410606
5.31	Kd	4900	nM	CHEMBL5426708

PubChem BioAssay actives

2 with measured affinity, of 9 total; 2 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
3-[8-chloro-3-[2-[(2-methoxyphenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-2-yl]propanoic acid	2010542: Binding affinity to N-terminal Avi-tagged and C-terminal His6-tagged USP16 (25 to 185 residues) (unknown origin) expressed in Escherichia coli BirA assessed as dissociation constant by SPR analysis	kd	1.3000	uM
3-[8-chloro-3-[2-[(2-methoxyphenyl)methyl-methylamino]-2-oxoethyl]-4-oxoquinazolin-2-yl]propanoic acid	2010542: Binding affinity to N-terminal Avi-tagged and C-terminal His6-tagged USP16 (25 to 185 residues) (unknown origin) expressed in Escherichia coli BirA assessed as dissociation constant by SPR analysis	kd	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
zinc chromate	increases expression, increases abundance	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
nickel acetate	affects expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	decreases expression	1
Succimer	increases expression, affects cotreatment	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gold	decreases expression	1
Lead	affects expression	1
Piroxicam	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Thimerosal	increases expression	1
Thiram	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4605980	Binding	Inhibition of USP16 (unknown origin)	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KZ	Abcam HEK293T USP16 KO	Transformed cell line	Female
CVCL_D6BE	HyCyte HEK293 KO-hUSP16	Transformed cell line	Female
CVCL_D6CL	HyCyte SH-SY5Y KO-hUSP16	Cancer cell line	Female
CVCL_TW61	HAP1 USP16 (-) 1	Cancer cell line	Male
CVCL_TW62	HAP1 USP16 (-) 2	Cancer cell line	Male
CVCL_TW63	HAP1 USP16 (-) 3	Cancer cell line	Male
CVCL_TW64	HAP1 USP16 (-) 4	Cancer cell line	Male
CVCL_TW65	HAP1 USP16 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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