OTUD6A

Summary

OTUD6A (OTU deubiquitinase 6A, HGNC:32312) is a protein-coding gene on chromosome Xq13.1, encoding OTU domain-containing protein 6A (Q7L8S5). Deubiquitinating enzyme that hydrolyzes ‘Lys-27’-, ‘Lys-29’- and ‘Lys-33’-linked polyubiquitin chains.

Deubiquitinating enzymes (DUBs; see MIM 603478) are proteases that specifically cleave ubiquitin (MIM 191339) linkages, negating the action of ubiquitin ligases. DUBA2 belongs to a DUB subfamily characterized by an ovarian tumor (OTU) domain.

Source: NCBI Gene 139562 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 20 total
• Druggable target: yes
• MANE Select transcript: NM_207320

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32312
Approved symbol	OTUD6A
Name	OTU deubiquitinase 6A
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25831, HSHIN6, DUBA2
Ensembl gene	ENSG00000189401
Ensembl biotype	protein_coding
OMIM	300714
Entrez	139562

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000338352

RefSeq mRNA: 1 — MANE Select: NM_207320 NM_207320

CCDS: CCDS14395

Canonical transcript exons

ENST00000338352 — 1 exons

Exon	Start	End
ENSE00001365531	70062457	70064179

Expression profiles

Bgee: expression breadth tissue_specific, 7 present calls, max score 75.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0096 / max 7.2174, expressed in 5 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196613	0.0096	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.64	gold quality
right testis	UBERON:0004534	65.98	gold quality
testis	UBERON:0000473	64.43	gold quality
left testis	UBERON:0004533	63.18	gold quality
sural nerve	UBERON:0015488	44.61	gold quality
bone marrow cell	CL:0002092	42.58	gold quality
cortical plate	UBERON:0005343	40.17	gold quality
granulocyte	CL:0000094	37.56	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
bone marrow	UBERON:0002371	35.02	gold quality
mucosa of transverse colon	UBERON:0004991	34.53	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
liver	UBERON:0002107	31.42	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
cerebellar hemisphere	UBERON:0002245	30.96	gold quality
cerebellum	UBERON:0002037	30.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	30.88	gold quality
cerebellar cortex	UBERON:0002129	30.86	gold quality
lymph node	UBERON:0000029	30.17	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
blood	UBERON:0000178	29.82	gold quality
prefrontal cortex	UBERON:0000451	29.49	gold quality
ascending aorta	UBERON:0001496	29.29	gold quality
leukocyte	CL:0000738	29.01	gold quality
thoracic aorta	UBERON:0001515	28.44	gold quality
duodenum	UBERON:0002114	28.14	gold quality
monocyte	CL:0000576	27.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting OTUD6A, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098

Literature-anchored findings (GeneRIF, showing 9)

• Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission. (PMID:33070427)
• OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase. (PMID:33669244)
• Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc. (PMID:35217790)
• OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR. (PMID:35233061)
• Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy. (PMID:35768646)
• Ovarian tumor deubiquitinase 6A regulates cell proliferation via deubiquitination of nucleolin and caspase7. (PMID:36082810)
• OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3. (PMID:38105755)
• Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING. (PMID:38342418)
• OTUD6A orchestrates complex modulation of TEAD4-mediated transcriptional programs. (PMID:38594215)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	otud4	ENSDARG00000077810
mus_musculus	Otud6a	ENSMUSG00000051582
rattus_norvegicus	Otud6a	ENSRNOG00000042687
drosophila_melanogaster	otu	FBGN0003023
drosophila_melanogaster	CG7857	FBGN0026738
drosophila_melanogaster	CG3251	FBGN0031622
caenorhabditis_elegans		WBGENE00009007

Paralogs (5): OTUD5 (ENSG00000068308), OTUD6B (ENSG00000155100), OTUD4 (ENSG00000164164), OTUD1 (ENSG00000165312), OTUD3 (ENSG00000169914)

Protein

Protein identifiers

OTU domain-containing protein 6A — Q7L8S5 (reviewed: Q7L8S5)

Alternative names: DUBA-2

All UniProt accessions (1): Q7L8S5

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that hydrolyzes ‘Lys-27’-, ‘Lys-29’- and ‘Lys-33’-linked polyubiquitin chains. Also able to hydrolyze ‘Lys-11’-linked ubiquitin chains.

RefSeq proteins (1): NP_997203* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003323	OTU_dom	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR049772	OTU_OTUD6	Domain
IPR050704	Peptidase_C85-like	Family

Pfam: PF02338

UniProt features (12 total): region of interest 5, active site 3, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L8S5-F1	83.01	0.44

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 (3): 152 (nucleophile); 268; 149

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 21 (showing top): GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, GOMF_UBIQUITIN_LIKE_PROTEIN_PEPTIDASE_ACTIVITY, chrXq13, GOBP_PROTEIN_K11_LINKED_DEUBIQUITINATION, MIR153_5P, MIR335_3P, MIR4533, MIR6876_5P, MIR4476, MIR504_3P, MIR10526_3P

GO Biological Process (6): proteolysis (GO:0006508), protein K29-linked deubiquitination (GO:0035523), protein K11-linked deubiquitination (GO:0035871), protein K27-linked deubiquitination (GO:1990167), protein K33-linked deubiquitination (GO:1990168), protein deubiquitination (GO:0016579)

GO Molecular Function (5): cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein deubiquitination	4
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1

Protein interactions and networks

STRING

446 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTUD6A	ZUP1	Q96AP4	916
OTUD6A	YOD1	Q5VVQ6	725
OTUD6A	OTUD1	Q5VV17	659
OTUD6A	OTUB2	Q96DC9	635
OTUD6A	OTUD7A	Q8TE49	629
OTUD6A	OTUD4	Q01804	613
OTUD6A	OTUD7B	Q6GQQ9	609
OTUD6A	OTUB1	Q96FW1	604
OTUD6A	VCPIP1	Q96JH7	570
OTUD6A	ZRANB1	Q9UGI0	567
OTUD6A	USP5	P45974	529
OTUD6A	ALG13	Q9NP73	524
OTUD6A	MYSM1	Q5VVJ2	519
OTUD6A	UCHL3	P15374	517
OTUD6A	USP26	Q9BXU7	503

IntAct

39 interactions, top by confidence:

A	B	Type	Score
DYNLL1	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
OTUD6A	PDLIM7	psi-mi:“MI:0915”(physical association)	0.560
NUP62	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
OTUD6A	VPS52	psi-mi:“MI:0915”(physical association)	0.560
OTUD6A	DYNLL2	psi-mi:“MI:0915”(physical association)	0.560
EMX2	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
OTUD6A	POM121	psi-mi:“MI:0915”(physical association)	0.560
OTUD6A	TRIM7	psi-mi:“MI:0915”(physical association)	0.560
SSBP1	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
DPYSL3	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
MYCL	OTUD6A	psi-mi:“MI:0915”(physical association)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CFTR	OTUD6A	psi-mi:“MI:0915”(physical association)	0.370
OTUD6A	DYNLL1	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	PDLIM7	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	NUP62	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	VPS52	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	DYNLL2	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	EMX2	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	POM121	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	TRIM7	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	DPYSL3	psi-mi:“MI:0915”(physical association)	0.000
OTUD6A	SSBP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (59): OTUD6A (Co-fractionation), OTUD6A (Affinity Capture-MS), OTUD6A (Two-hybrid), OTUD6A (Two-hybrid), OTUD6A (Two-hybrid), OTUD6A (Two-hybrid), OTUD6A (Two-hybrid), OTUD6A (Two-hybrid), POM121 (Two-hybrid), PDLIM7 (Two-hybrid), NUP62 (Two-hybrid), VPS52 (Two-hybrid), DYNLL2 (Two-hybrid), Akt1 (Biochemical Activity), OTUD6A (Affinity Capture-Western)

ESM2 similar proteins: A0AUR5, A8XDJ2, B0WTN3, B2RYG6, B3MCZ5, B3NRC6, B4GDM5, B4HR14, B4JW83, B4KT65, B4LJT9, B4MY75, B4P6M6, B4QFD2, P38747, P52788, P97355, Q05B57, Q0IH43, Q0V9S0, Q17D30, Q17QF2, Q292F0, Q29FC9, Q3SZA5, Q4VSI4, Q567B1, Q5ZJM3, Q6A4J8, Q6IE21, Q6NTW6, Q6NX27, Q6U7I1, Q7JVI3, Q7L8S5, Q7Q068, Q7TQI3, Q7ZV00, Q803R5, Q93009

Diamond homologs: B1AZ99, B2RRE7, F4K3M6, Q01804, Q0V869, Q2YDU3, Q3U2S4, Q5T2D3, Q5ZIP6, Q6IE21, Q7L8S5, Q7ZX21, Q8LBW2, Q9D8C3, Q9NP73, Q9XIP2, P38747, Q6GM06, Q8K2H2, Q8N6M0, Q9UUK3, Q5M8L0, Q7ZV00, Q9LYC7, Q8LBZ4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

68 predictions. Top by Δscore:

Variant	Effect	Δscore
X:70063188:C:G	donor_gain	0.4600
X:70063121:C:G	donor_gain	0.4400
X:70063230:A:AG	donor_gain	0.4200
X:70063268:G:GG	donor_gain	0.4200
X:70063173:G:T	donor_gain	0.4100
X:70063231:T:G	donor_gain	0.4100
X:70063267:A:AG	donor_gain	0.4100
X:70063446:G:GG	donor_gain	0.4100
X:70063069:TCGAC:T	donor_gain	0.4000
X:70063120:GC:G	donor_gain	0.3800
X:70063265:GGA:G	donor_gain	0.3800
X:70063266:GAG:G	donor_gain	0.3800
X:70063154:C:G	donor_gain	0.3700
X:70063173:G:GT	donor_gain	0.3700
X:70063400:GCGC:G	donor_gain	0.3700
X:70063443:TCA:T	donor_gain	0.3700
X:70063174:G:T	donor_gain	0.3600
X:70063441:CCTCA:C	donor_gain	0.3600
X:70063444:CA:C	donor_gain	0.3600
X:70063052:C:G	donor_gain	0.3400
X:70063155:G:GG	donor_gain	0.3400
X:70063443:TCAGT:T	donor_loss	0.3400
X:70063444:CAG:C	donor_loss	0.3400
X:70063445:AGTAG:A	donor_loss	0.3400
X:70063446:G:A	donor_loss	0.3400
X:70063447:T:G	donor_loss	0.3400
X:70063229:GATCC:G	donor_gain	0.3300
X:70063263:GAGGA:G	donor_gain	0.3300
X:70063277:G:GT	donor_gain	0.3300
X:70063160:C:T	donor_gain	0.3200

AlphaMissense

1911 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:70062990:G:C	A156P	0.986
X:70063077:T:C	F185L	0.972
X:70063079:C:A	F185L	0.972
X:70063079:C:G	F185L	0.972
X:70063189:T:C	L222P	0.967
X:70063086:T:C	F188L	0.964
X:70063088:C:A	F188L	0.964
X:70063088:C:G	F188L	0.964
X:70063035:C:A	R171S	0.959
X:70063201:C:G	S226W	0.959
X:70063187:G:C	E221D	0.958
X:70063187:G:T	E221D	0.958
X:70063047:G:C	A175P	0.957
X:70063131:T:C	F203L	0.957
X:70063133:C:A	F203L	0.957
X:70063133:C:G	F203L	0.957
X:70063195:C:A	A224D	0.957
X:70063198:T:C	L225P	0.955
X:70062984:T:G	Y154D	0.952
X:70062985:A:C	Y154S	0.952
X:70062988:G:C	R155P	0.951
X:70063222:T:A	I233N	0.951
X:70063261:G:T	G246V	0.949
X:70062991:C:A	A156D	0.948
X:70063200:T:C	S226P	0.948
X:70063078:T:C	F185S	0.947
X:70062946:T:C	L141P	0.946
X:70063210:T:C	L229P	0.946
X:70063260:G:T	G246W	0.946
X:70062994:T:A	I157N	0.944

dbSNP variants (sampled 300 via entrez): RS1000406206 (X:70062067 C>A,T), RS1003448566 (X:70062065 A>G), RS1004202132 (X:70062837 G>GA), RS1004379444 (X:70063501 T>C), RS1006433795 (X:70062150 C>T), RS1006440024 (X:70062439 C>A,T), RS1008325473 (X:70064674 T>C), RS1008610139 (X:70061506 A>T), RS1009371678 (X:70064148 T>A,C,G), RS1010293888 (X:70061649 G>A), RS1010407192 (X:70061222 C>T), RS1011290456 (X:70063388 G>A), RS1011405354 (X:70063050 A>G), RS1012315989 (X:70061743 G>A), RS1012912563 (X:70063527 C>A,T)

Disease associations

OMIM: gene MIM:300714 | 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): CHEMBL4630842 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Valproic Acid	increases methylation	1
Particulate Matter	decreases expression, increases abundance	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
CHEMBL4605999	Binding	Inhibition of human His6-tagged OTUD6A expressed in Escherichia coli assessed as cleavage of Ubiquitin-Rhodamine110-glycine to Ubiquitin and Rhodamine110-glycine using Ubiquitin-Rhodamine110-glycine as substrate by fluorescence based analys	Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity. — J Med Chem

Clinical trials (associated diseases)

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