ZUP1

Summary

ZUP1 (zinc finger containing ubiquitin peptidase 1, HGNC:21224) is a protein-coding gene on chromosome 6q22.1, encoding Zinc finger-containing ubiquitin peptidase 1 (Q96AP4). Deubiquitinase with endodeubiquitinase activity that specifically interacts with and cleaves ‘Lys-63’-linked long polyubiquitin chains.

This gene encodes a protein containing zinc finger motifs and a cysteine peptidase domain. The encoded protein functions as a K63-specific de-ubiquitinating enzyme that specifically cleaves long K63-linked polyubiquitin chains in the middle of a chain (i.e. “endo cleavage) rather than by removing the terminal ubiquitin from a chain. This enzyme is thought to be involved in the regulation of DNA repair by cleaving K63-linked ubiquitin chains at repair foci. This protein is related to proteases for the ubiquitin-like modifiers Ufm1 (ubiquitin fold modifier 1) and Atg8/Gabarapl2, but does not have any activity on these modifiers.

Source: NCBI Gene 221302 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 90 total
• MANE Select transcript: NM_145062

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21224
Approved symbol	ZUP1
Name	zinc finger containing ubiquitin peptidase 1
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ412I7.3
Ensembl gene	ENSG00000153975
Ensembl biotype	protein_coding
OMIM	620543
Entrez	221302

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000368573, ENST00000368576, ENST00000471919, ENST00000485498, ENST00000905911, ENST00000905912, ENST00000935654, ENST00000935655, ENST00000935656, ENST00000935657, ENST00000945047

RefSeq mRNA: 4 — MANE Select: NM_145062 NM_001361189, NM_001361190, NM_001361191, NM_145062

CCDS: CCDS5110

Canonical transcript exons

ENST00000368576 — 10 exons

Exon	Start	End
ENSE00000975521	116645714	116645934
ENSE00001084507	116647459	116647610
ENSE00001084513	116666634	116667207
ENSE00001084516	116651572	116651737
ENSE00003470354	116658803	116658924
ENSE00003524674	116656684	116656852
ENSE00003591464	116635618	116635879
ENSE00003607929	116652004	116652192
ENSE00003614676	116660736	116660846
ENSE00003848001	116668566	116668766

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 91.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.0911 / max 114.8289, expressed in 1714 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75269	8.0451	1714
75268	0.0460	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.47	gold quality
cortical plate	UBERON:0005343	88.71	gold quality
oocyte	CL:0000023	87.42	gold quality
monocyte	CL:0000576	86.30	gold quality
leukocyte	CL:0000738	85.86	gold quality
jejunal mucosa	UBERON:0000399	85.47	gold quality
lower esophagus mucosa	UBERON:0035834	84.46	gold quality
duodenum	UBERON:0002114	84.33	gold quality
skin of abdomen	UBERON:0001416	84.26	gold quality
skin of leg	UBERON:0001511	83.76	gold quality
bone marrow	UBERON:0002371	83.53	gold quality
ganglionic eminence	UBERON:0004023	83.37	gold quality
body of pancreas	UBERON:0001150	83.31	gold quality
granulocyte	CL:0000094	83.27	gold quality
islet of Langerhans	UBERON:0000006	82.76	gold quality
ventricular zone	UBERON:0003053	82.43	gold quality
adrenal tissue	UBERON:0018303	82.39	gold quality
zone of skin	UBERON:0000014	82.33	gold quality
right lung	UBERON:0002167	82.29	gold quality
rectum	UBERON:0001052	82.26	gold quality
pancreas	UBERON:0001264	82.15	gold quality
esophagus mucosa	UBERON:0002469	81.89	gold quality
upper lobe of left lung	UBERON:0008952	81.32	gold quality
cerebellar hemisphere	UBERON:0002245	81.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.14	gold quality
cerebellar cortex	UBERON:0002129	81.08	gold quality
calcaneal tendon	UBERON:0003701	81.08	gold quality
spleen	UBERON:0002106	81.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting ZUP1, 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-548AW	99.99	72.57	3559
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-4705	99.10	69.10	1091
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-331-5P	96.59	67.94	705

Literature-anchored findings (GeneRIF, showing 5)

• ZUFSP (ZUP1) is a K63-specific deubiquitinating enzyme that is distantly related to proteases for the ubiquitin-like modifiers Ufm1 and Atg8. ZUFSP does not have any activity on these modifiers. ZUFSP specifically cleaves long K63-linked poly-ubiquitin chains in an ““endo”” mode, i.e. cleavage takes place in the middle of a chain rather than by removing the terminal ubiquitin from a chain. (PMID:29476094)
• ZUFSP,the singular human member of this family, which contains multiple ubiquitin-binding domains responsible for the specific action on K63-linked chains. (PMID:29476094)
• Identify two ubiquitin binding domains in ZUFSP: a ZHA (ZUFSP helical arm) that binds to the distal ubiquitin and an atypical UBZ domain in ZUFSP that binds to polyubiquitin. Importantly, both domains are essential for ZUFSP to selectively cleave K63-linked polyubiquitin. (PMID:29576527)
• ZUFSP is recruited to and regulates K63-Ub conjugates at genotoxic stress sites, promoting chromosome stability upon replication stress in a manner dependent on its catalytic activity. (PMID:29576528)
• Functional Analysis of Single Nucleotide Polymorphism in ZUFSP Protein and Implication in Pathogenesis. (PMID:33512633)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Zup1	ENSMUSG00000039531
rattus_norvegicus	Zup1	ENSRNOG00000000398
drosophila_melanogaster	dwg	FBGN0000520
drosophila_melanogaster	CG6654	FBGN0038301
caenorhabditis_elegans		WBGENE00003933

Paralogs (6): ZNF324 (ENSG00000083812), ZBTB47 (ENSG00000114853), GTF3A (ENSG00000122034), ZNF513 (ENSG00000163795), ZNF652 (ENSG00000198740), ZNF324B (ENSG00000249471)

Protein

Protein identifiers

Zinc finger-containing ubiquitin peptidase 1 — Q96AP4 (reviewed: Q96AP4)

Alternative names: Lys-63-specific deubiquitinase ZUFSP, Zinc finger with UFM1-specific peptidase domain protein

All UniProt accessions (3): Q96AP4, A0A0S2Z644, X6R6X3

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase with endodeubiquitinase activity that specifically interacts with and cleaves ‘Lys-63’-linked long polyubiquitin chains. Shows only weak activity against ‘Lys-11’ and ‘Lys-48’-linked chains. Plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage. Modulates the ubiquitination status of replication protein A (RPA) complex proteins in response to replication stress.

Subunit / interactions. Interacts with RPA1 and RPA2.

Subcellular location. Cytoplasm. Nucleus.

Domain organisation. The motif interacting with ubiquitin (MIU) and ZUFSP ubiquitin-binding domain (zUBD, also called ZUFSP helical arm ZHA) are responsible for binding the distal (outgoing) ubiquitin units S1 and S2 respectively. C2H2-type zinc finger 4 is a ubiquitin-binding zinc finger (UBZ) and required for polyubiquitin binding, possibly binding the proximal ubiqutin, and for catalytic activity. C2H2-type zinc fingers 1-3 are required for localization to sites of DNA damage.

Similarity. Belongs to the peptidase C78 family. ZUFSP subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96AP4-1	1	yes
Q96AP4-2	2

RefSeq proteins (4): NP_001348118, NP_001348119, NP_001348120, NP_659499* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012462	UFSP1/2_DUB_cat	Domain
IPR013087	Znf_C2H2_type	Domain
IPR050688	Zinc_finger/UBP_domain	Family

Pfam: PF07910

UniProt features (50 total): helix 17, strand 9, mutagenesis site 7, zinc finger region 4, turn 3, active site 3, region of interest 2, chain 1, site 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6EI1	X-RAY DIFFRACTION	1.73
6FGE	X-RAY DIFFRACTION	1.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AP4-F1	80.08	0.57

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 (4): 487 (involved in the stabilization of negative charge on the oxyanion by the formation of the oxyanion hole); 360 (nucleophile); 491 (proton acceptor); 512

Post-translational modifications (1): 262

Mutagenesis-validated functional residues (7):

Position	Phenotype
351	no effect.
360	loss of catalytic activity.
406	loss of catalytic activity.
428	loss of catalytic activity.
487	loss of catalytic activity.
491	loss of catalytic activity.
512	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 91 (showing top): FOSTER_TOLERANT_MACROPHAGE_UP, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOMF_PEPTIDASE_ACTIVITY, chr6q22, GOMF_UBIQUITIN_LIKE_PROTEIN_PEPTIDASE_ACTIVITY, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, BAKKER_FOXO3_TARGETS_UP, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, GSE14415_INDUCED_VS_NATURAL_TREG_UP, GSE14415_NATURAL_TREG_VS_FOXP3_KO_NATURAL_TREG_DN, GSE13547_2H_VS_12_H_ANTI_IGM_STIM_ZFX_KO_BCELL_UP, ELF2_TARGET_GENES, ZNF197_TARGET_GENES, ZNF85_TARGET_GENES, MIR570_3P

GO Biological Process (0):

GO Molecular Function (5): cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZUP1	USP12	O75317	938
ZUP1	OTUD1	Q5VV17	927
ZUP1	USP30	Q70CQ3	925
ZUP1	STAMBPL1	Q96FJ0	917
ZUP1	OTUD6B	Q8N6M0	916
ZUP1	OTUD6A	Q7L8S5	916
ZUP1	USP17L2	Q6R6M4	912
ZUP1	USP1	O94782	910
ZUP1	YOD1	Q5VVQ6	898
ZUP1	OTUB1	Q96FW1	891
ZUP1	USP8	P40818	885
ZUP1	USP14	P54578	871
ZUP1	UCHL3	P15374	858
ZUP1	ZNF629	Q9UEG4	856
ZUP1	ZNF501	Q96CX3	856

IntAct

18 interactions, top by confidence:

A	B	Type	Score
ZUP1	RPS21	psi-mi:“MI:0915”(physical association)	0.560
RPS21	ZUP1	psi-mi:“MI:0915”(physical association)	0.560
ARHGAP45	ZUP1	psi-mi:“MI:0915”(physical association)	0.560
MMP14	ZUP1	psi-mi:“MI:0915”(physical association)	0.560
TCEAL1	CHEK1	psi-mi:“MI:0914”(association)	0.530
CDKN2A	ZUP1	psi-mi:“MI:0915”(physical association)	0.370
CFTR	ZUP1	psi-mi:“MI:0915”(physical association)	0.370
SHCBP1	ZUP1	psi-mi:“MI:0915”(physical association)	0.370
PRMT5	ZUP1	psi-mi:“MI:0915”(physical association)	0.370
sseF	SNAP23	psi-mi:“MI:2364”(proximity)	0.270
ARHGAP45	ZUP1	psi-mi:“MI:0915”(physical association)	0.000
MMP14	ZUP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (200): ZUFSP (Two-hybrid), ZUFSP (Affinity Capture-RNA), ZUFSP (Affinity Capture-MS), ZUFSP (Two-hybrid), ZUFSP (Affinity Capture-MS), ZUFSP (Two-hybrid), UBC (Biochemical Activity), UBC (Co-crystal Structure), RPA1 (Affinity Capture-MS), RPA2 (Affinity Capture-MS), RPA3 (Affinity Capture-MS), SSBP1 (Affinity Capture-MS), USP11 (Affinity Capture-MS), UBR5 (Affinity Capture-MS), UBC (Affinity Capture-MS)

ESM2 similar proteins: A0A1P8ASY1, A3KMI0, A5HEI1, A6QQR4, B3M268, B4IJG7, B4NJW0, B4PUD1, B4QUC0, B9EUM5, B9FL70, D1KF50, F1Q514, F4HZF0, F4I9Q5, F4IBQ9, F4J2M6, F4J394, F4JX00, O81635, P36607, P38859, Q09142, Q09811, Q0IMS9, Q0PCS3, Q1EHT7, Q3SWY8, Q4R4A2, Q56Y74, Q6P158, Q7Y1C4, Q7Y1C5, Q84M98, Q8L840, Q8S949, Q8W103, Q8W1Y3, Q941I6, Q96AP4

Diamond homologs: O13979, Q3SWY8, Q3T9Z9, Q4R4A2, Q5U2S3, Q96AP4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1593 predictions. Top by Δscore:

Variant	Effect	Δscore
6:116645706:ATACT:A	donor_loss	1.0000
6:116645707:TACTT:T	donor_loss	1.0000
6:116645708:ACT:A	donor_loss	1.0000
6:116645709:CT:C	donor_loss	1.0000
6:116645710:TTACA:T	donor_loss	1.0000
6:116645711:TACA:T	donor_loss	1.0000
6:116645712:A:AC	donor_gain	1.0000
6:116645712:ACA:A	donor_loss	1.0000
6:116645713:C:A	donor_loss	1.0000
6:116645713:C:CC	donor_gain	1.0000
6:116645713:CA:C	donor_gain	1.0000
6:116645713:CAA:C	donor_gain	1.0000
6:116645713:CAAG:C	donor_gain	1.0000
6:116645713:CAAGT:C	donor_gain	1.0000
6:116647589:G:C	acceptor_gain	1.0000
6:116658799:GTAC:G	donor_loss	1.0000
6:116658800:TACCT:T	donor_loss	1.0000
6:116658935:T:TC	acceptor_gain	1.0000
6:116635881:T:C	acceptor_gain	0.9900
6:116645705:GATAC:G	donor_loss	0.9900
6:116645932:GACC:G	acceptor_loss	0.9900
6:116645935:C:CC	acceptor_gain	0.9900
6:116645936:T:G	acceptor_loss	0.9900
6:116647587:T:C	acceptor_gain	0.9900
6:116647587:T:TC	acceptor_gain	0.9900
6:116651570:A:AC	donor_gain	0.9900
6:116651571:C:CC	donor_gain	0.9900
6:116651575:AC:A	donor_gain	0.9900
6:116651576:CC:C	donor_gain	0.9900
6:116651603:CT:C	donor_gain	0.9900

AlphaMissense

3834 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:116645927:A:C	S492R	0.995
6:116645927:A:T	S492R	0.995
6:116645929:T:G	S492R	0.995
6:116652065:T:A	R363S	0.994
6:116652065:T:G	R363S	0.994
6:116652066:C:G	R363T	0.994
6:116645925:C:G	R493P	0.993
6:116647470:A:G	L486P	0.993
6:116652062:A:C	N364K	0.993
6:116652062:A:T	N364K	0.993
6:116645913:C:T	G497E	0.992
6:116645919:A:T	V495D	0.992
6:116652082:A:G	W358R	0.992
6:116652082:A:T	W358R	0.992
6:116645761:A:C	Y548D	0.991
6:116651687:A:G	W401R	0.991
6:116651687:A:T	W401R	0.991
6:116652066:C:A	R363I	0.991
6:116667102:A:G	C31R	0.990
6:116651621:A:G	W423R	0.989
6:116651621:A:T	W423R	0.989
6:116660823:A:G	C195R	0.989
6:116652091:C:G	D355H	0.988
6:116647592:A:C	F445L	0.987
6:116647592:A:T	F445L	0.987
6:116647594:A:G	F445L	0.987
6:116652080:C:A	W358C	0.987
6:116652080:C:G	W358C	0.987
6:116651690:C:G	A400P	0.986
6:116651706:T:A	Q394H	0.986

dbSNP variants (sampled 300 via entrez): RS1000004685 (6:116636011 T>C), RS1000006489 (6:116638972 C>A,G,T), RS1000106954 (6:116643467 A>C,G), RS1000138104 (6:116643318 A>T), RS1000202045 (6:116657930 A>G), RS1000223863 (6:116661770 A>G), RS1000324387 (6:116651198 T>C), RS1000327918 (6:116666454 T>A,C), RS1000381686 (6:116650833 C>T), RS1000561203 (6:116659948 G>A), RS1000594979 (6:116666647 G>A), RS1000642380 (6:116653295 A>G), RS1000661404 (6:116652814 T>C), RS1000672145 (6:116639161 G>A,C), RS1000715447 (6:116653086 A>AC)

Disease associations

OMIM: gene MIM:620543 | 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: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
methylparaben	increases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzene	increases expression	1
Cisplatin	decreases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, increases expression	1
Succimer	affects cotreatment, increases expression	1
Gold	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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