USP39

Summary

USP39 (ubiquitin specific peptidase 39, HGNC:20071) is a protein-coding gene on chromosome 2p11.2, encoding Ubiquitin carboxyl-terminal hydrolase 39 (Q53GS9). Deubiquitinating enzyme that plays a role in many cellular processes including cellular antiviral response, epithelial morphogenesis, DNA repair or B-cell development. It is a common-essential gene (DepMap: required in 98.2% of cancer cell lines).

Predicted to enable cysteine-type deubiquitinase activity and zinc ion binding activity. Involved in spliceosomal complex assembly. Located in nucleoplasm. Part of U4/U6 x U5 tri-snRNP complex.

Source: NCBI Gene 10713 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 94 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_006590

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20071
Approved symbol	USP39
Name	ubiquitin specific peptidase 39
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Aliases	SAD1, CGI-21, SNRNP65
Ensembl gene	ENSG00000168883
Ensembl biotype	protein_coding
OMIM	611594
Entrez	10713

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 17 protein_coding, 9 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000323701, ENST00000409025, ENST00000409470, ENST00000409766, ENST00000442708, ENST00000448971, ENST00000450066, ENST00000455732, ENST00000458268, ENST00000459775, ENST00000465282, ENST00000465514, ENST00000467885, ENST00000474572, ENST00000481409, ENST00000490193, ENST00000491659, ENST00000493829, ENST00000496047, ENST00000613444, ENST00000860349, ENST00000860350, ENST00000860351, ENST00000860352, ENST00000860353, ENST00000860354, ENST00000916017, ENST00000916018, ENST00000946314

RefSeq mRNA: 5 — MANE Select: NM_006590 NM_001256725, NM_001256726, NM_001256727, NM_001256728, NM_006590

CCDS: CCDS33234, CCDS58716, CCDS58717, CCDS74534

Canonical transcript exons

ENST00000323701 — 13 exons

Exon	Start	End
ENSE00001893724	85616186	85616463
ENSE00003466064	85648761	85649283
ENSE00003470137	85636053	85636130
ENSE00003479656	85621485	85621579
ENSE00003502497	85619220	85619289
ENSE00003518597	85644948	85645083
ENSE00003535152	85630721	85630946
ENSE00003543997	85625539	85625691
ENSE00003582788	85637369	85637436
ENSE00003592711	85640976	85641118
ENSE00003614151	85639203	85639391
ENSE00003651344	85623646	85623782
ENSE00003653940	85647930	85648016

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 96.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.3941 / max 505.7435, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21229	47.6193	1823
21225	2.7968	1442
21226	2.0270	949
21233	0.6081	272
21227	0.4163	206
21230	0.3337	120
21232	0.3056	133
21228	0.2872	142

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.20	gold quality
ganglionic eminence	UBERON:0004023	95.18	gold quality
gastrocnemius	UBERON:0001388	94.53	gold quality
granulocyte	CL:0000094	94.09	gold quality
muscle of leg	UBERON:0001383	94.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.93	gold quality
monocyte	CL:0000576	93.14	gold quality
embryo	UBERON:0000922	92.99	gold quality
leukocyte	CL:0000738	92.84	gold quality
cortical plate	UBERON:0005343	92.76	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.76	gold quality
lower esophagus	UBERON:0013473	92.75	gold quality
mononuclear cell	CL:0000842	92.74	gold quality
stromal cell of endometrium	CL:0002255	92.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.43	gold quality
upper lobe of left lung	UBERON:0008952	92.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.40	gold quality
right lung	UBERON:0002167	92.38	gold quality
right coronary artery	UBERON:0001625	92.32	gold quality
popliteal artery	UBERON:0002250	92.31	gold quality
tibial artery	UBERON:0007610	92.31	gold quality
mucosa of transverse colon	UBERON:0004991	92.29	gold quality
body of uterus	UBERON:0009853	92.27	gold quality
ectocervix	UBERON:0012249	92.13	gold quality
skin of leg	UBERON:0001511	92.09	gold quality
apex of heart	UBERON:0002098	92.09	gold quality
islet of Langerhans	UBERON:0000006	92.05	gold quality
rectum	UBERON:0001052	92.05	gold quality
muscle organ	UBERON:0001630	92.05	gold quality
left coronary artery	UBERON:0001626	91.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.83
E-ENAD-17	no	382.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting USP39, 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-6508-5P	99.92	70.67	2465
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-676-5P	98.49	68.87	1492
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-10400-3P	97.29	64.66	597
HSA-MIR-4674	97.29	64.62	597
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 34)

• These observations suggest Usp39 to be involved in splicing of Aurora B and other mRNAs that are essential for proper spindle checkpoint function. (PMID:18728397)
• These results suggest that USP39 may act as an oncogenic factor in breast cancer and could be a potential molecular target for breast cancer gene therapy. (PMID:24126978)
• Inducible knockdown of USP39 or overexpression of USP39 in TNBC cells. (PMID:25812575)
• Our data indicate that USP39 knockdown inhibited the growth of HCC both in vitro and in vivo through G2/M arrest, which was partly achieved via the inhibition of FoxM1 splicing. (PMID:26081192)
• The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of prostate cancer (PMID:26959883)
• shRNA-mediated knockdown of USP39 inhibited the growth and colony formation ability of GC cells. suppression of USP39 induced G2/M-phase arrest and increased the cleavage of PARP (Asp214). (PMID:27175747)
• USP39 is upregulated in melanoma tissues and that it is implicated in melanoma progression by regulating cell cycle and apoptosis via ERK1/2 signal pathways. (PMID:27456357)
• study indicates that USP39 may be functionally involved in lung cancer growth and act as a potential molecular target for human lung cancer diagnosis and treatment. (PMID:27629785)
• High USP39 expression is associated with colon and lung cancer. (PMID:28154181)
• Results show a significantly higher expression of USP39 in colorectal cancer tissues and cell lines and provide evidence that USP39 protein plays an important role in the growth and metastasis of colorectal cancer mainly through Wnt/beta-catenin pathway. (PMID:28259917)
• Data show that knockdown of ubiquitin specific peptidase 39 (USP39), a direct target of microRNA microRNA-133a, induced cell apoptosis through inhibition of proto-oncogene proteins c-akt (AKT) signaling pathway in pancreatic cancer (PC) cells. (PMID:28286270)
• Knockdown of USP39 expression in osteosarcoma cell line U2OS cell significantly decreased cell proliferation, impaired colony formation ability. A further analysis indicated suppression of USP39 arrested cell cycle progression at G2/M phase via p21 dependent way. In addition, the results of Annexin V/7-AAD staining suggested the knockdown of USP39 could promote U2OS cell apoptosis through PARP cleavage. (PMID:28403900)
• Data suggest that ZIP, USP39, Prp24/p100/SART3, and Prp43 associate to form complex instrumental in spliceosome assembly; ZIP regulates pre-mRNA splicing of USP39 independent of RNA binding; stable 35S tri-snRNP particles are enriched in Cajal body. (ZIP = zinc finger and G-patch domain-containing protein; SART3 = squamous cell carcinoma antigen recognised by T cells 3; Prp43 = RNA helicase Prp43) (PMID:28878014)
• Results demonstrated that USP39 deubiquitinates and stabilizes CHK2, which in turn regulates cell cycle checkpoint, cell apoptosis and chemo-radiation response. Furthermore, USP39 and CHK2 are correlatively downregulated in lung cancer, suggesting a potential prognostic role of USP39 in lung cancer. (PMID:30771428)
• Study confirmed that USP39 was highly expressed in nasopharyngeal carcinoma (NPC) tissues, and its overexpression promoted NPC cell proliferation, while its silencing suppressed it. Further data predicted USP39 as a direct target of miR-26b at its 3’-UTR mRNA. (PMID:30898716)
• USP39 promotes the development of human leukemia by regulating cell cycle, survival, and proliferation of the cells. (PMID:30898977)
• Findings of this study suggest that USP39 may paly a vital role in regulating ovarian cancer malignant phenotypes and carboplatin resistance. (PMID:31180526)
• USP39 has oncogenic properties that increase TAZ protein levels by inducing maturation of its mRNA. USP39 therefore provides a novel therapeutic target for the treatment of human glioma. (PMID:31332287)
• USP39 was frequently overexpressed in human ovarian cancer and was highly correlated with TNM stage. Suppression of USP39 markedly inhibited the growth and migration of ovarian cancer cell lines HO-8910 and SKOV3 and induced cell cycle G2/M arrest. (PMID:31637536)
• USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN-Induced Antiviral Immunity. (PMID:33127822)
• Knocking down USP39 Inhibits the Growth and Metastasis of Non-Small-Cell Lung Cancer Cells through Activating the p53 Pathway. (PMID:33255748)
• USP39 mediates p21-dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis. (PMID:33634905)
• Ubiquitin-specific peptidase 39 promotes human glioma cells migration and invasion by facilitating ADAM9 mRNA maturation. (PMID:33811456)
• USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma. (PMID:34197957)
• circRNA derived from CLSPN (circCLSPN) is an oncogene in human glioblastoma multiforme by regulating cell growth, migration and invasion via ceRNA pathway. (PMID:34269180)
• USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing. (PMID:34614178)
• The spliceosome component Usp39 controls B cell development by regulating immunoglobulin gene rearrangement. (PMID:35139388)
• miR-381 Inhibits Proliferation and Invasion of Non-Small-Cell Cancer Cells by Targeting USP39. (PMID:36046375)
• USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC. (PMID:37821439)
• USP39-Mediated Non-Proteolytic Control of ETS2 Suppresses Nuclear Localization and Activity. (PMID:37892157)
• USP39 interacts with SIRT7 to promote cervical squamous cell carcinoma by modulating autophagy and oxidative stress via FOXM1. (PMID:37957720)
• Deubiquitinase USP39 promotes SARS-CoV-2 replication by deubiquitinating and stabilizing the envelope protein. (PMID:38158131)
• USP39 Promotes the Viability and Migration of Head and Neck Squamous Cell Carcinoma Cell by Regulating STAT1. (PMID:38706215)
• Deubiquitinating enzyme USP39 promotes the growth and metastasis of gastric cancer cells by modulating the degradation of RNA-binding protein RBM39. (PMID:39260689)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp39	ENSDARG00000041908
mus_musculus	Usp39	ENSMUSG00000056305
rattus_norvegicus	Usp39	ENSRNOG00000010930
drosophila_melanogaster	Usp39	FBGN0030969
caenorhabditis_elegans		WBGENE00017280

Paralogs (2): USP46 (ENSG00000109189), USP12 (ENSG00000152484)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 39 — Q53GS9 (reviewed: Q53GS9)

Alternative names: SAD1 homolog, U4/U6.U5 tri-snRNP-associated 65 kDa protein

All UniProt accessions (7): A0A087WW31, A0A087X1B2, B9A018, C9J0X5, C9JIU2, Q53GS9, F8WC91

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that plays a role in many cellular processes including cellular antiviral response, epithelial morphogenesis, DNA repair or B-cell development. Plays a role in pre-mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the precatalytic spliceosome. Specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus and therefore plays an essential role in B-cell development. Regulates AURKB mRNA levels, and thereby plays a role in cytokinesis and in the spindle checkpoint. Regulates apoptosis and G2/M cell cycle checkpoint in response to DNA damage by deubiquitinating and stabilizing CHK2. Also plays an important role in DNA repair by controlling the recruitment of XRCC4/LIG4 to DNA double-strand breaks for non-homologous end-joining repair. Participates in antiviral activity by affecting the type I IFN signaling by stabilizing STAT1 and decreasing its ‘Lys-6’-linked ubiquitination. Contributes to non-canonical Wnt signaling during epidermal differentiation. Acts as a negative regulator NF-kappa-B activation through deubiquitination of ‘Lys-48’-linked ubiquitination of NFKBIA.

Subunit / interactions. The U4/U6-U5 tri-snRNP complex is a building block of the precatalytic spliceosome (spliceosome B complex). Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39, plus LSM2, LSM3, LSM4, LSM5, LSM6, LSM7 and LSM8.

Subcellular location. Nucleus.

Similarity. Belongs to the peptidase C19 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q53GS9-1	1	yes
Q53GS9-2	2
Q53GS9-3	3

RefSeq proteins (5): NP_001243654, NP_001243655, NP_001243656, NP_001243657, NP_006581* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR028889	USP	Domain
IPR033809	USP39	Family
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF02148

UniProt features (80 total): strand 31, helix 16, sequence conflict 7, turn 7, binding site 4, splice variant 3, compositionally biased region 3, modified residue 2, region of interest 2, chain 1, domain 1, cross-link 1, mutagenesis site 1, zinc finger region 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
6QW6	ELECTRON MICROSCOPY	2.92
8QOZ	ELECTRON MICROSCOPY	3.1
8QPE	ELECTRON MICROSCOPY	3.1
8H6E	ELECTRON MICROSCOPY	3.2
8H6J	ELECTRON MICROSCOPY	3.25
6QX9	ELECTRON MICROSCOPY	3.28
8Y6O	ELECTRON MICROSCOPY	3.38
8QP8	ELECTRON MICROSCOPY	3.5
8QPA	ELECTRON MICROSCOPY	3.7
8QPB	ELECTRON MICROSCOPY	3.7
8QP9	ELECTRON MICROSCOPY	4.1
8QZS	ELECTRON MICROSCOPY	4.1
8QPK	ELECTRON MICROSCOPY	4.2
8R09	ELECTRON MICROSCOPY	4.3
8R0B	ELECTRON MICROSCOPY	4.4
6AH0	ELECTRON MICROSCOPY	5.7
8R0A	ELECTRON MICROSCOPY	5.8
8R08	ELECTRON MICROSCOPY	6.1
8RM5	ELECTRON MICROSCOPY	6.9
3JCR	ELECTRON MICROSCOPY	7
8QXD	ELECTRON MICROSCOPY	9.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53GS9-F1	79.30	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 155; 161; 136; 139

Post-translational modifications (3): 46, 82, 51

Mutagenesis-validated functional residues (1):

Position	Phenotype
306	complete loss of chk2 and nfkbia deubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway

MSigDB gene sets: 141 (showing top): PAX4_01, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, WONG_PROTEASOME_GENE_MODULE, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_SPLICEOSOMAL_TRI_SNRNP_COMPLEX_ASSEMBLY, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, REACTOME_MRNA_SPLICING, chr2p11, FISCHER_DREAM_TARGETS, DOUGLAS_BMI1_TARGETS_UP, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS

GO Biological Process (6): spliceosomal complex assembly (GO:0000245), mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), RNA splicing (GO:0008380), protein deubiquitination (GO:0016579), cell division (GO:0051301)

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

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), U4/U6 x U5 tri-snRNP complex (GO:0046540)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
mRNA Splicing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
mRNA splicing, via spliceosome	1
protein-RNA complex assembly	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
cellular process	1
transition metal ion binding	1
catalytic activity	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
U5 snRNP	1
U4/U6 snRNP	1
spliceosomal tri-snRNP complex	1

Protein interactions and networks

STRING

1730 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP39	SNRNP27	Q8WVK2	940
USP39	TRIM44	Q96DX7	890
USP39	USP5	P45974	755
USP39	DDX23	Q9BUQ8	685
USP39	USP13	Q92995	671
USP39	PRPF3	O43395	667
USP39	PRPF6	O94906	654
USP39	ZRANB1	Q9UGI0	652
USP39	FJX1	Q86VR8	636
USP39	USP25	Q9UHP3	632
USP39	USP14	P54578	623
USP39	USP45	Q70EL2	611
USP39	SNRNP70	P08621	608
USP39	PAN2	Q504Q3	604
USP39	USP7	Q93009	597

IntAct

86 interactions, top by confidence:

A	B	Type	Score
CD2BP2	SNRNP200	psi-mi:“MI:0914”(association)	0.800
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
PRPF8	PRPF4	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
SNRNP40	PRPF4	psi-mi:“MI:0914”(association)	0.640
PRP4K	PRPF4	psi-mi:“MI:0914”(association)	0.640
USP39	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.590
SRPK1	USP39	psi-mi:“MI:0217”(phosphorylation reaction)	0.590
USP12	PHLPP1	psi-mi:“MI:0914”(association)	0.570
SNRPE	PRMT5	psi-mi:“MI:0914”(association)	0.530
SNRNP40	AQR	psi-mi:“MI:0914”(association)	0.530
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
USP39	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
Prpf8		psi-mi:“MI:0915”(physical association)	0.400
PRPF4		psi-mi:“MI:0914”(association)	0.350
Chmp3	DTL	psi-mi:“MI:0914”(association)	0.350
Sart1	PRPF4	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
DDX41	DDX39A	psi-mi:“MI:0914”(association)	0.350
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
KSR1	FAM168B	psi-mi:“MI:0914”(association)	0.350
KSR1		psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
RAB27A	DKC1	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
POC5	DSC2	psi-mi:“MI:0914”(association)	0.350

BioGRID (319): USP39 (Affinity Capture-MS), USP39 (Affinity Capture-MS), USP39 (Affinity Capture-MS), ADARB1 (Co-fractionation), CSNK1E (Co-fractionation), LGALS9 (Co-fractionation), NSUN2 (Co-fractionation), PCNA (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation), USP39 (Co-fractionation)

ESM2 similar proteins: A0A0G2JTR4, A4FUN7, A5D9H7, A5WWB0, A6H8I0, A6NNY8, A6QNS3, C0HB46, D0RB01, E1C1R4, F1M625, O24454, O75317, P09851, P0C8Z3, P20936, P50904, P62068, P62069, Q09LZ8, Q12979, Q16288, Q3TIX9, Q52KZ6, Q53GS9, Q5DU02, Q5F415, Q5F450, Q5IFJ9, Q5IS37, Q5IS82, Q5M981, Q5R573, Q5R761, Q5R8I6, Q5RBQ4, Q5RDP3, Q5SSL4, Q60969, Q6DCJ1

Diamond homologs: A4FUN7, A5D9H7, A5WWB0, A6H8I0, A6NNY8, A6QR55, A6ZY34, A7TGY3, B1AY15, B2GUX4, B2GUZ1, B3LGK1, C0HB46, D0RB01, E1B9W9, E9Q9U0, F1M625, F6Z5C0, G5E8G2, G5E8I7, M9PD06, O22207, O60079, O60139, O74442, O75317, O94966, O96612, P0C8Z3, P32571, P35123, P35125, P39538, P39944, P50102, P51784, P62068, P62069, Q01988, Q0E2F9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
USP39	“form complex”	“U4/U6.U5 snRNP complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Metabolism of non-coding RNA	5	40.1×	6e-06
mRNA Splicing	21	29.2×	1e-23
mRNA Splicing - Minor Pathway	10	28.3×	9e-11
Processing of Capped Intron-Containing Pre-mRNA	23	23.9×	1e-23
mRNA Splicing - Major Pathway	33	22.8×	2e-34
mRNA Polyadenylation	17	18.9×	1e-15
CHD1 and CHD2 subfamily	13	17.9×	2e-11
SARS-CoV-2 modulates host translation machinery	6	17.0×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	9	60.4×	3e-12
spliceosomal snRNP assembly	9	56.2×	4e-12
RNA splicing, via transesterification reactions	8	53.7×	2e-10
spliceosomal complex assembly	8	51.8×	2e-10
regulation of mRNA splicing, via spliceosome	5	47.7×	4e-06
mRNA splicing, via spliceosome	30	29.5×	9e-34
RNA splicing	17	16.1×	1e-13
mRNA processing	12	10.2×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2855 predictions. Top by Δscore:

Variant	Effect	Δscore
2:85609429:GCGTA:G	donor_loss	1.0000
2:85609430:CGTA:C	donor_loss	1.0000
2:85609432:TACCT:T	donor_loss	1.0000
2:85609434:C:CG	donor_loss	1.0000
2:85609584:CAT:C	acceptor_gain	1.0000
2:85609601:CACAG:C	acceptor_gain	1.0000
2:85616454:G:GT	donor_gain	1.0000
2:85616454:G:T	donor_gain	1.0000
2:85616460:CGAG:C	donor_loss	1.0000
2:85616461:GAGG:G	donor_loss	1.0000
2:85616462:AGGTG:A	donor_loss	1.0000
2:85616463:GG:G	donor_loss	1.0000
2:85616464:GT:G	donor_loss	1.0000
2:85616465:T:G	donor_loss	1.0000
2:85619218:A:AG	acceptor_gain	1.0000
2:85619219:G:GA	acceptor_gain	1.0000
2:85619219:GC:G	acceptor_gain	1.0000
2:85619219:GCAA:G	acceptor_gain	1.0000
2:85619219:GCAAA:G	acceptor_gain	1.0000
2:85619285:AACAG:A	donor_loss	1.0000
2:85619288:AGG:A	donor_loss	1.0000
2:85619290:G:GC	donor_loss	1.0000
2:85619291:T:G	donor_loss	1.0000
2:85621205:A:AG	acceptor_gain	1.0000
2:85621206:G:GG	acceptor_gain	1.0000
2:85621484:GGA:G	acceptor_gain	1.0000
2:85621484:GGAGT:G	acceptor_gain	1.0000
2:85625534:TGCA:T	acceptor_loss	1.0000
2:85625535:GCA:G	acceptor_loss	1.0000
2:85625536:CAG:C	acceptor_loss	1.0000

AlphaMissense

3726 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:85619264:T:A	C105S	1.000
2:85619264:T:C	C105R	1.000
2:85619265:G:A	C105Y	1.000
2:85619265:G:C	C105S	1.000
2:85619266:C:G	C105W	1.000
2:85619274:T:C	L108P	1.000
2:85619283:T:A	I111N	1.000
2:85621493:T:C	L116P	1.000
2:85621495:G:C	D117H	1.000
2:85621498:T:C	F118L	1.000
2:85621500:T:A	F118L	1.000
2:85621500:T:G	F118L	1.000
2:85621501:G:C	D119H	1.000
2:85621502:A:T	D119V	1.000
2:85621504:T:C	F120L	1.000
2:85621506:T:A	F120L	1.000
2:85621506:T:G	F120L	1.000
2:85621516:T:A	C124S	1.000
2:85621516:T:C	C124R	1.000
2:85621517:G:A	C124Y	1.000
2:85621517:G:C	C124S	1.000
2:85621517:G:T	C124F	1.000
2:85621518:T:G	C124W	1.000
2:85621550:C:A	A135D	1.000
2:85621552:T:A	C136S	1.000
2:85621552:T:C	C136R	1.000
2:85621553:G:A	C136Y	1.000
2:85621553:G:C	C136S	1.000
2:85621553:G:T	C136F	1.000
2:85621554:T:G	C136W	1.000

dbSNP variants (sampled 300 via entrez): RS1000033559 (2:85605076 A>G), RS1000102395 (2:85629322 A>G), RS1000106784 (2:85605460 T>C), RS1000211109 (2:85612206 C>A,T), RS1000351466 (2:85611292 A>G,T), RS1000358 (2:85620926 A>G), RS1000359 (2:85620579 A>G), RS1000361529 (2:85616340 C>G), RS1000382429 (2:85617607 A>G), RS1000410980 (2:85612056 C>T), RS1000476223 (2:85629137 C>T), RS1000569836 (2:85633576 C>T), RS1000600918 (2:85633836 T>C), RS1000632184 (2:85633963 A>G), RS1000709861 (2:85633216 G>A,T)

Disease associations

OMIM: gene MIM:611594 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008821_6	Neurofibrillary tangles	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006797	neurofibrillary tangles measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291601 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases expression, decreases expression	2
sodium arsenite	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Cisplatin	decreases reaction, increases abundance, increases expression, decreases response to substance	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Mercury	increases expression	1
Methyl Methanesulfonate	increases expression	1
Naled	affects expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Reactive Oxygen Species	decreases reaction, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228942	Binding	Binding affinity to biotinylated USP39 zinc finger ubiquitin binding domain (84 to 194 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay	Structure-Activity Relationship of USP5 Inhibitors. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KX	N/Tert-1 USP39	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

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