USP51

Summary

USP51 (ubiquitin specific peptidase 51, HGNC:23086) is a protein-coding gene on chromosome Xp11.21, encoding Ubiquitin carboxyl-terminal hydrolase 51 (Q70EK9). Specifically deubiquitinates ‘Lys-14’ (H2AK13Ub) and ‘Lys-16’(H2AK15Ub) of histone H2A regulating the DNA damage response at double-strand breaks (DSBs).

Enables chromatin binding activity; deubiquitinase activity; and histone binding activity. Involved in DNA repair-dependent chromatin remodeling; regulation of cell cycle process; and regulation of double-strand break repair. Predicted to be located in chromosome.

Source: NCBI Gene 158880 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 83 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_201286

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23086
Approved symbol	USP51
Name	ubiquitin specific peptidase 51
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000247746
Ensembl biotype	protein_coding
Entrez	158880

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000500968, ENST00000586165, ENST00000933765, ENST00000959739

RefSeq mRNA: 1 — MANE Select: NM_201286 NM_201286

CCDS: CCDS14370

Canonical transcript exons

ENST00000500968 — 3 exons

Exon	Start	End
ENSE00002039456	55489169	55489365
ENSE00002050185	55484616	55488988
ENSE00003919384	55489776	55489848

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 96.04.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	96.04	gold quality
oviduct epithelium	UBERON:0004804	90.15	gold quality
caput epididymis	UBERON:0004358	83.97	gold quality
kidney epithelium	UBERON:0004819	83.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.67	gold quality
adrenal tissue	UBERON:0018303	82.55	gold quality
bronchial epithelial cell	CL:0002328	82.14	gold quality
pigmented layer of retina	UBERON:0001782	81.53	gold quality
cauda epididymis	UBERON:0004360	81.25	gold quality
bronchus	UBERON:0002185	81.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.05	gold quality
endothelial cell	CL:0000115	77.81	silver quality
buccal mucosa cell	CL:0002336	76.96	silver quality
mucosa of paranasal sinus	UBERON:0005030	76.41	silver quality
fallopian tube	UBERON:0003889	75.83	gold quality
germinal epithelium of ovary	UBERON:0001304	73.91	silver quality
islet of Langerhans	UBERON:0000006	73.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	71.67	gold quality
right adrenal gland cortex	UBERON:0035827	71.45	gold quality
stromal cell of endometrium	CL:0002255	71.31	gold quality
left ventricle myocardium	UBERON:0006566	71.05	gold quality
ventricular zone	UBERON:0003053	70.81	gold quality
parietal pleura	UBERON:0002400	70.17	gold quality
smooth muscle tissue	UBERON:0001135	69.66	gold quality
tibia	UBERON:0000979	69.56	silver quality
right adrenal gland	UBERON:0001233	69.52	gold quality
right uterine tube	UBERON:0001302	69.32	gold quality
adrenal gland	UBERON:0002369	69.32	gold quality
calcaneal tendon	UBERON:0003701	69.06	gold quality
cortical plate	UBERON:0005343	68.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting USP51, 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-4283	100.00	66.42	2097
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
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-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 6)

• USP51 is the deubiquitylating enzyme for H2AK13,15ub and regulates DNA damage response (PMID:27083998)
• ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes, including USP27x and USP51, and that imbalances in these activities likely potentiate human diseases including cancer. (PMID:27132940)
• CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism. (PMID:32296027)
• The role of USP51 in attenuating chemosensitivity of lung cancer cells to cisplatin by regulating DNA damage response. (PMID:35856403)
• USP51 promotes non-small cell lung carcinoma cell stemness by deubiquitinating TWIST1. (PMID:37422632)
• USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A. (PMID:37816999)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Usp51	ENSMUSG00000067215
rattus_norvegicus	Usp51	ENSRNOG00000021434

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), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 51 — Q70EK9 (reviewed: Q70EK9)

Alternative names: Deubiquitinating enzyme 51, Ubiquitin thioesterase 51, Ubiquitin-specific-processing protease 51

All UniProt accessions (2): Q70EK9, A0A1B0GVA6

UniProt curated annotations — full annotation on UniProt →

Function. Specifically deubiquitinates ‘Lys-14’ (H2AK13Ub) and ‘Lys-16’(H2AK15Ub) of histone H2A regulating the DNA damage response at double-strand breaks (DSBs). USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of TP53BP1 and BRCA1. Functions in DNA double-strand break repair also by mediating the deubiquitination and subsequent stabilization of DGCR8, leading to the recruitment of DGCR8 binding partners to double strand breaks such as RNF168 or MDC1. In addition, promotes the deubiquitination and stabilization of the transcriptional repressor ZEB1.

Subunit / interactions. Interacts with H2A.

Subcellular location. Chromosome.

Tissue specificity. Expressed in prostate, brain, lung, aorta and kidney.

Induction. By ionizing radiation (IR).

Similarity. Belongs to the peptidase C19 family.

RefSeq proteins (1): NP_958443* (*=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
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF02148

UniProt features (27 total): binding site 12, compositionally biased region 6, mutagenesis site 3, active site 2, chain 1, domain 1, zinc finger region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q70EK9-F1	69.28	0.43

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): 372 (nucleophile); 665 (proton acceptor)

Ligand- & substrate-binding residues (12): 195; 197; 236; 239; 249; 252; 257; 262; 266; 272; 285; 288

Mutagenesis-validated functional residues (3):

Position	Phenotype
372	abolishes ability to deubiquitinate histone h2a; when associated with 665-r. no decrease of total h2ak15ub levels follow
372	complete loss of deubiquitinase activity.
665	abolishes ability to deubiquitinate histone h2a; when associated with 665-r. suppresses ionizing radiation-induced h2ak1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 93 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_REGULATION_OF_DNA_REPAIR, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, ZIC1_01, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_STRESS, HAND1E47_01

GO Biological Process (8): DNA repair (GO:0006281), proteolysis (GO:0006508), DNA damage response (GO:0006974), regulation of cell cycle process (GO:0010564), regulation of double-strand break repair via homologous recombination (GO:0010569), protein deubiquitination (GO:0016579), DNA repair-dependent chromatin remodeling (GO:0140861), regulation of double-strand break repair via nonhomologous end joining (GO:2001032)

GO Molecular Function (9): chromatin binding (GO:0003682), cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), histone binding (GO:0042393), histone H2A deubiquitinase activity (GO:0140950), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA damage response	2
regulation of double-strand break repair	2
DNA metabolic process	1
protein metabolic process	1
cellular response to stress	1
cell cycle process	1
regulation of cell cycle	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
chromatin remodeling	1
double-strand break repair via nonhomologous end joining	1
binding	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
protein binding	1
histone deubiquitinase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP51	ENY2	Q9NPA8	887
USP51	ATXN7L3	Q14CW9	844
USP51	ZUP1	Q96AP4	639
USP51	ZEB1	P37275	524
USP51	FAT4	Q6V0I7	508
USP51	ATXN7	O15265	465
USP51	OTUB1	Q96FW1	456
USP51	PAN2	Q504Q3	454
USP51	OTUD6A	Q7L8S5	452
USP51	RNF169	Q8NCN4	436
USP51	CDK4	P11802	435
USP51	RNF168	Q8IYW5	433
USP51	OTUD7A	Q8TE49	432
USP51	RNF40	O75150	432
USP51	UCHL1	P09936	431

IntAct

7 interactions, top by confidence:

A	B	Type	Score
ATXN7L3	USP27X	psi-mi:“MI:0914”(association)	0.640
PB2		psi-mi:“MI:0914”(association)	0.350
PRMT2	KRBA1	psi-mi:“MI:0914”(association)	0.350
USP51	GSTA1	psi-mi:“MI:0914”(association)	0.350
USP51	USP27X	psi-mi:“MI:0914”(association)	0.350

BioGRID (119): HIST2H2AC (Affinity Capture-Western), HIST2H2AC (Biochemical Activity), ZEB1 (Affinity Capture-Western), USP51 (Affinity Capture-Western), ZEB1 (Reconstituted Complex), HIST1H2AB (Biochemical Activity), HIST1H2BB (Biochemical Activity), USP51 (Affinity Capture-Western), FAT4 (Affinity Capture-Western), USP51 (Affinity Capture-Western), ZEB1 (Affinity Capture-Western), USP51 (Reconstituted Complex), CDK4 (Affinity Capture-Western), CDK6 (Affinity Capture-Western), USP51 (Reconstituted Complex)

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: A4FUN7, A5PMR2, A5PN09, A6H8I0, A6NNY8, A6QNM7, A6QR55, A7Z056, A8MUK1, B1AY15, B1WBD7, B2GUZ1, B2RQC2, C9JJH3, C9JLJ4, C9JPN9, C9JVI0, D3ZU96, D6R901, D6R9N7, D6RA61, D6RBM5, D6RBQ6, D6RCP7, D6RJB6, E1B9W9, F6Z5C0, M9PD06, O22207, O60079, O75604, O94966, P0C8Z3, P35123, P39538, P40818, P50102, P51784, Q09738, Q0WX57

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	65
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599604	NM_201286.4(USP51):c.13C>T (p.Arg5Ter)	Pathogenic

SpliceAI

552 predictions. Top by Δscore:

Variant	Effect	Δscore
X:55487089:C:CT	acceptor_gain	0.9800
X:55487090:A:T	acceptor_gain	0.9800
X:55486846:CCCT:C	donor_gain	0.9700
X:55488989:C:CC	acceptor_gain	0.9700
X:55486398:G:C	donor_gain	0.9600
X:55488696:T:A	donor_gain	0.9500
X:55489126:A:C	donor_gain	0.9300
X:55486865:T:TA	donor_gain	0.9000
X:55488986:CGA:C	acceptor_gain	0.9000
X:55487088:C:G	acceptor_gain	0.8900
X:55488991:G:C	acceptor_gain	0.8900
X:55488995:A:C	acceptor_gain	0.8900
X:55488749:CGCT:C	donor_gain	0.8800
X:55486862:AAGT:A	donor_gain	0.8700
X:55488984:TGCGA:T	acceptor_gain	0.8700
X:55489094:AG:A	donor_gain	0.8700
X:55485606:T:G	acceptor_gain	0.8600
X:55487089:C:T	acceptor_gain	0.8600
X:55485605:T:TG	acceptor_gain	0.8500
X:55486845:AC:A	donor_gain	0.8500
X:55486846:CC:C	donor_gain	0.8500
X:55488688:GAGCA:G	donor_loss	0.8500
X:55488689:AGCAC:A	donor_loss	0.8500
X:55488690:GCAC:G	donor_loss	0.8500
X:55488691:CACCT:C	donor_loss	0.8500
X:55488692:AC:A	donor_loss	0.8500
X:55488693:C:A	donor_loss	0.8500
X:55489163:GGTTA:G	donor_loss	0.8400
X:55489164:GTTA:G	donor_loss	0.8400
X:55489165:TTA:T	donor_loss	0.8400

AlphaMissense

4705 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:55486895:T:A	D682V	1.000
X:55486895:T:C	D682G	1.000
X:55486895:T:G	D682A	1.000
X:55486896:C:A	D682Y	1.000
X:55486896:C:G	D682H	1.000
X:55486911:A:G	W677R	1.000
X:55486911:A:T	W677R	1.000
X:55486944:A:G	Y666H	1.000
X:55486945:G:C	H665Q	1.000
X:55486945:G:T	H665Q	1.000
X:55486947:G:C	H665D	1.000
X:55486949:C:A	G664V	1.000
X:55486949:C:T	G664D	1.000
X:55486950:C:G	G664R	1.000
X:55486964:C:A	G659V	1.000
X:55486964:C:T	G659E	1.000
X:55486965:C:G	G659R	1.000
X:55486965:C:T	G659R	1.000
X:55486969:G:C	H657Q	1.000
X:55486969:G:T	H657Q	1.000
X:55486971:G:C	H657D	1.000
X:55486971:G:T	H657N	1.000
X:55487143:A:C	F599L	1.000
X:55487143:A:T	F599L	1.000
X:55487145:A:G	F599L	1.000
X:55487149:C:A	K597N	1.000
X:55487149:C:G	K597N	1.000
X:55487197:T:A	K581N	1.000
X:55487197:T:G	K581N	1.000
X:55487460:A:G	S494P	1.000

dbSNP variants (sampled 300 via entrez): RS1000090055 (X:55489369 A>T), RS1000902230 (X:55485031 G>A), RS1001083686 (X:55486166 G>T), RS1001729477 (X:55490714 A>C,G), RS1002133142 (X:55485271 T>C), RS1002524921 (X:55485701 G>A), RS1003946186 (X:55487932 A>C), RS1004208952 (X:55488084 A>C,G), RS1005090762 (X:55484430 A>G), RS1005612 (X:55491806 T>A,C), RS1005619153 (X:55490110 G>A), RS1005754927 (X:55489866 G>A,T), RS1006804583 (X:55484287 G>A), RS1007930872 (X:55486265 C>T), RS1008409193 (X:55485873 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002396_25	Smoking initiation	8.000000e-08
GCST006011_35	Mean corpuscular volume	3.000000e-08
GCST006442_454	Educational attainment (years of education)	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005670	smoking initiation
EFO:0004784	self reported educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291536 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
Nickel	decreases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
sodium arsenite	increases expression	1
ferrous chloride	decreases expression	1
hydroquinone	decreases expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Fonofos	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Parathion	increases methylation	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Acrylamide	increases expression	1
S-Nitrosoglutathione	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228944	Binding	Binding affinity to biotinylated USP51 zinc finger ubiquitin binding domain (176 to 305 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay	Structure-Activity Relationship of USP5 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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