CDC34

Summary

CDC34 (cell division cycle 34, ubiquitin conjugating enzyme, HGNC:1734) is a protein-coding gene on chromosome 19p13.3, encoding Ubiquitin-conjugating enzyme E2 R1 (P49427). E2 ubiquitin-conjugating enzyme that accepts ubiquitin from an E1 ubiquitin-activating protein, and catalyzes its covalent attachment to other proteins by an E3 ubiquitin-protein ligase complex.

The protein encoded by this gene is a member of the ubiquitin-conjugating enzyme family. Ubiquitin-conjugating enzyme catalyzes the covalent attachment of ubiquitin to other proteins. This protein is a part of the large multiprotein complex, which is required for ubiquitin-mediated degradation of cell cycle G1 regulators, and for the initiation of DNA replication.

Source: NCBI Gene 997 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 43 total — 1 pathogenic
• MANE Select transcript: NM_004359

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1734
Approved symbol	CDC34
Name	cell division cycle 34, ubiquitin conjugating enzyme
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	E2-CDC34, UBE2R1, UBC3
Ensembl gene	ENSG00000099804
Ensembl biotype	protein_coding
OMIM	116948
Entrez	997

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000215574, ENST00000586283, ENST00000586788, ENST00000593036, ENST00000606065, ENST00000606400, ENST00000607527, ENST00000874791, ENST00000874792, ENST00000874793

RefSeq mRNA: 1 — MANE Select: NM_004359 NM_004359

CCDS: CCDS12030

Canonical transcript exons

ENST00000215574 — 5 exons

Exon	Start	End
ENSE00000655676	531760	532108
ENSE00000655678	536243	536340
ENSE00000655679	537013	537147
ENSE00000655680	541339	542087
ENSE00003643788	535837	535923

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.0587 / max 767.7012, expressed in 1820 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172687	19.5079	1804
172686	18.2800	1804
172688	0.5141	290
172683	0.3361	92
172689	0.2128	86
172685	0.1802	64
172684	0.0275	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.47	gold quality
right testis	UBERON:0004534	97.33	gold quality
lower esophagus mucosa	UBERON:0035834	97.05	gold quality
apex of heart	UBERON:0002098	97.04	gold quality
ventricular zone	UBERON:0003053	96.98	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.74	gold quality
cerebellar hemisphere	UBERON:0002245	96.48	gold quality
cerebellar cortex	UBERON:0002129	96.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.18	gold quality
ganglionic eminence	UBERON:0004023	96.15	gold quality
right lobe of liver	UBERON:0001114	96.09	gold quality
gastrocnemius	UBERON:0001388	96.01	gold quality
blood	UBERON:0000178	95.96	gold quality
mucosa of transverse colon	UBERON:0004991	95.85	gold quality
right frontal lobe	UBERON:0002810	95.74	gold quality
adenohypophysis	UBERON:0002196	95.67	gold quality
muscle of leg	UBERON:0001383	95.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.49	gold quality
lower esophagus	UBERON:0013473	95.48	gold quality
testis	UBERON:0000473	95.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.26	gold quality
skin of leg	UBERON:0001511	95.19	gold quality
right atrium auricular region	UBERON:0006631	95.16	gold quality
granulocyte	CL:0000094	94.76	gold quality
heart left ventricle	UBERON:0002084	94.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.76	gold quality
cerebellum	UBERON:0002037	94.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.63	gold quality
mucosa of stomach	UBERON:0001199	94.48	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	12.78
E-HCAD-13	yes	7.57
E-MTAB-6524	no	72.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

32 targeting CDC34, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-1244	99.33	68.38	832
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-6878-5P	98.49	67.91	2142

Literature-anchored findings (GeneRIF, showing 26)

• degraded by HSV-1 ICP0 while stabilizing cyclins D1 and D3 (PMID:14645576)
• antisense oligonucleotides targeting the human ubiquitin-conjugating enzyme Cdc34 downregulate its expression, inhibit the degradation of p27Kip1, and prevent cellular proliferation (PMID:15652359)
• although a Cdc34 mutant bearing a deletion of the C-terminal 36 amino acids (Cdc34 1-200) was efficiently charged with ubiquitin by E1, it was severely reduced for the ability to ubiquitinate p27(Kip1) in vitro compared to wildtype Cdc34 (PMID:16123592)
• Data suggest that the Skp1.CUL1.F-box-mediated polyubiquitination reaction may require the conversion of Cdc34 from an inactive monomer to a highly active dimeric form. (PMID:16210246)
• in vivo phosphorylation sites on budding yeast Cdc34 (yCdc34; Ser207 and Ser216) and human Cdc34 (hCdc34 Ser203, Ser222 and Ser231) to serine residues in the acidic tail domain, a region that is critical for Cdc34’s cell cycle function (PMID:17461777)
• In tissue culture cells, Uba6 is required for charging a previously uncharacterized Uba6-specific E2 (Use1), whereas Ube1 is required for charging the cell-cycle E2s Cdc34A and Cdc34B (PMID:17597759)
• These findings support the hypothesis that human Cdc34 S95 and E108/E112 are required to position the donor ubiquitin optimally for catalysis, in a manner that might depend on E2 dimerization. (PMID:17698585)
• cisplatin increased ATF5 protein expression via preventing its ubiquitin-dependent degradation, which might be associated with its promoting the nucleus-to-cytoplasm translocation of E2 ubiquitin-conjugating enzyme Cdc34 (PMID:18458088)
• Cdc34 is a functional target of let-7 and that let-7 induces down-regulation of Cdc34, stabilization of the Wee1 kinase, and an increased fraction of cells in G(2)/M in primary fibroblasts. (PMID:19126550)
• The acidic tail of the Cdc34 ubiquitin-conjugating enzyme functions in both binding to and catalysis with ubiquitin ligase SCFCdc4. (PMID:19875449)
• Study shows that chain assembly by ubiquitin ligase SCF and ubiquitin-conjugating enzyme Cdc34 is facilitated by the unusual nature of Cdc34-SCF transactions: Cdc34 binds SCF with nanomolar affinity, nevertheless the complex is extremely dynamic. (PMID:19945379)
• determined that a ubiquitin (Ub) fused at I kappaB alpha K21 acts as a receptor, directing Cdc34 for rapid and efficient K48-linked Ub chain synthesis that depends on SCF(beta TrCP2) and the substrate’s N terminus. (PMID:20347421)
• the human Cdc34 carboxyl terminus contains a non-covalent ubiquitin binding activity that contributes to SCF-dependent ubiquitination (PMID:20353940)
• COP9 signalosome protects ubiquitin-conjugating enzyme 3 (UBC3/Cdc34) from beta-transducin repeat-containing protein (betaTrCP)-mediated degradation (PMID:20378537)
• work provides the first structural details that show how the C-terminus of CDC34 might direct a thiolester-bound Ub to control polyubiquitin chain formation (PMID:21296085)
• Tristetraprolin promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. (PMID:22210895)
• Data show that anaphase-promoting complex or cyclosome (APC/C)-mediated multiple monoubiquitylation targeting cyclin B1 for degradation. (PMID:22286100)
• These data suggest that FBXO15 and Ube2r1 regulate P-gp expression through the ubiquitin-proteasome pathway. (PMID:23465077)
• Here we have investigated how the acidic loop in human Cdc34 promotes ubiquitination, identifying two key molecular events during which the acidic loop exerts its influence (PMID:24129577)
• We discuss how these results can explain the rapid association of Cdc34 and SCF. (PMID:25425648)
• ubiquitin binding by the acidic loops of Ube2g1 and Ube2r1 enzymes distinguishes their Lys-48-ubiquitylation activities (PMID:25471371)
• Study shows that Ube2R1/2 forms a salt bridge interaction between a conserved Asp residue on Ube2R1/2 and acceptor ubiquitin residue Arg 54 and that perturbation of this interaction leads to the severe loss of UbeR2 activity. Results also provide new insight into how the Ube2R1/2 acidic loop may participate in catalysis. (PMID:27044868)
• study finds that mutation of the catalytically active cysteine to serine (C93S) results in the reduced ubiquitination, increased stability, and attenuated degradation rate of CDC34; Through semi-quantitative proteomics, identified the CDC34-interacting proteins and discovered that the wild-type and mutant proteins have many differentially interacted proteins (PMID:29564676)
• UBE2R2 alone had negligible ubiquitylation activity at physiological concentrations and the ablation of UBE2R1/2 had no effect on the stability of SCF substrates in cells. A genome-wide CRISPR screen revealed that an additional E2 enzyme, UBE2G1, buffers against the loss of UBE2R1/2. (PMID:31868589)
• Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis. (PMID:32114396)
• Targeting CDC34 E2 ubiquitin conjugating enzyme for lung cancer therapy. (PMID:32268269)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdc34	ENSMUSG00000020307
mus_musculus	Cdc34b	ENSMUSG00000020870
rattus_norvegicus	Cdc34	ENSRNOG00000060530

Paralogs (24): UBE2T (ENSG00000077152), UBE2A (ENSG00000077721), UBE2K (ENSG00000078140), UBE2I (ENSG00000103275), UBE2W (ENSG00000104343), UBE2R2 (ENSG00000107341), UBE2S (ENSG00000108106), UBE2B (ENSG00000119048), UBE2G1 (ENSG00000132388), UBE2Z (ENSG00000159202), UBE2J2 (ENSG00000160087), AKTIP (ENSG00000166971), UBE2V2 (ENSG00000169139), UBE2C (ENSG00000175063), UBE2O (ENSG00000175931), UBE2U (ENSG00000177414), UBE2N (ENSG00000177889), UBE2F (ENSG00000184182), UBE2G2 (ENSG00000184787), UBE2H (ENSG00000186591), UBE2J1 (ENSG00000198833), PEDS1 (ENSG00000240849), UBE2V1 (ENSG00000244687), UBE2NL (ENSG00000276380)

Protein

Protein identifiers

Ubiquitin-conjugating enzyme E2 R1 — P49427 (reviewed: P49427)

Alternative names: (E3-independent) E2 ubiquitin-conjugating enzyme R1, E2 ubiquitin-conjugating enzyme R1, Ubiquitin-conjugating enzyme E2-32 kDa complementing, Ubiquitin-conjugating enzyme E2-CDC34, Ubiquitin-protein ligase R1

All UniProt accessions (4): P49427, U3KPV8, U3KQ77, U3KQP9

UniProt curated annotations — full annotation on UniProt →

Function. E2 ubiquitin-conjugating enzyme that accepts ubiquitin from an E1 ubiquitin-activating protein, and catalyzes its covalent attachment to other proteins by an E3 ubiquitin-protein ligase complex. In vitro catalyzes ‘Lys-48’-linked polyubiquitination. Cooperates with the E2 UBCH5C and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Performs ubiquitin chain elongation building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 acts as an initiator E2, priming the phosphorylated NFKBIA target at positions ‘Lys-21’ and/or ‘Lys-22’ with a monoubiquitin. Cooperates with the SCF(SKP2) E3 ligase complex to regulate cell proliferation through ubiquitination and degradation of MYBL2 and KIP1. Involved in ubiquitin conjugation and degradation of CREM isoform ICERIIgamma and ATF15 resulting in abrogation of ICERIIgamma- and ATF5-mediated repression of cAMP-induced transcription during both meiotic and mitotic cell cycles. Involved in the regulation of the cell cycle G2/M phase through its targeting of the WEE1 kinase for ubiquitination and degradation. Also involved in the degradation of beta-catenin. Is target of human herpes virus 1 protein ICP0, leading to ICP0-dependent dynamic interaction with proteasomes.

Subunit / interactions. Interacts with multiple Cul1-RING E3 ubiquitin-protein ligase complexes, also known as SCF (SKP1-CUL1-F-box protein) complexes. Identified in a SCF E3 ubiquitin ligase complex together with HINT1 and RBX1. When cullin is neddylated, the interaction between the E2 and the SCF complex is strengthened. Interacts with multiple Cul2-RING (CRL2) E3 ubiquitin-protein ligase complexes, also known as ECS (Elongin BC-CUL2/5-SOCS-box protein) complexes. When phosphorylated, interacts with beta-TrCP (BTRC). Interacts with human herpes virus 1 protein ICP0 and associates with the proteasome for degradation. Interacts with casein kinase subunit CSNK2B. Interacts with CNTD1; this interaction regulates the cell-cycle progression.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in testes during spermatogenesis to regulate repression of cAMP-induced transcription.

Post-translational modifications. Autoubiquitinated. Autoubiquitination is promoted by the human herpes virus 1 protein ICP0 and leads to degradation by the Ubiquitin-proteasomal pathway. Phosphorylated by CK2. Phosphorylation of the C-terminal tail by CK2 controls the nuclear localization.

Activity regulation. CDC34-catalyzed polyubiquitin chain assembly activity is stimulated by the conjugation of NEDD8 to the CUL1 SCF E3 ligase complex subunit.

Domain organisation. The C-terminal acidic tail is required for nuclear localization and is involved in the binding to SCF E3 ligase complexes, and more specifically with the CUL1 subunit.

Induction. Negatively regulated by the let-7 microRNA.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-conjugating enzyme family.

RefSeq proteins (1): NP_004350* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000608	UBC	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR023313	UBQ-conjugating_AS	Active_site
IPR050113	Ub_conjugating_enzyme-E2-like	Family

Pfam: PF00179

Enzyme classification (BRENDA):

• EC 2.3.2.23 — E2 ubiquitin-conjugating enzyme (BRENDA: 20 organisms, 93 substrates, 28 inhibitors, 12 Km, 8 kcat entries)
• EC 2.3.2.24 — (E3-independent) E2 ubiquitin-conjugating enzyme (BRENDA: 5 organisms, 56 substrates, 7 inhibitors, 6 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBIQUITIN-CARRIER-PROTEIN UBC2B]-L-CYSTEINE	0.0001	5
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.2203–0.3014	2
[HISTONE H2A]-L-LYSINE	0.0008–0.0028	2
[HISTONE H2B]-L-LYSINE	0.0015–0.012	2
S-UBIQUITINYL-[E1 UBIQUITIN-ACTIVATING ENZYME]-L	1	1
[UBIQUITIN CARRIER PROTEIN UBC4]-L-CYSTEINE	0.0019	1
[CYTOCHROME C]-L-LYSINE	0.125	1
[HISTONE H3]-L-LYSINE	0.0013	1

UniProt features (51 total): mutagenesis site 26, modified residue 5, helix 5, strand 5, region of interest 3, turn 3, chain 1, domain 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3RZ3	X-RAY DIFFRACTION	2.3
2OB4	X-RAY DIFFRACTION	2.4
7M2K	X-RAY DIFFRACTION	2.47
4MDK	X-RAY DIFFRACTION	2.61
8RX0	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49427-F1	85.52	0.71

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 (1): 93 (glycyl thioester intermediate)

Post-translational modifications (5): 236, 203, 222, 231, 233

Mutagenesis-validated functional residues (26):

Position	Phenotype
70	loss of rbx1-binding.
85	inhibits both mono and polyubiquitination of nfkbia.
87	decreases polyubiquitination of nfkbia.
93	loss of function.
95	inhibits both mono and polyubiquitination of nfkbia.
97	loss of function.
102	inhibits polyubiquitination of nfkbia; when associated with a-103.
103	inhibits polyubiquitination of nfkbia; when associated with a-102.
108	decrease in substrate affinity and ubiquitin transfer rate for neddylated crl2(fem1c)-ube2r1 complex. inhibits both mono
112	inhibits both mono and polyubiquitination of nfkbia; when associated with a-108.
113	decrease in substrate affinity and ubiquitin transfer rate for neddylated crl2(fem1c)-ube2r1 complex.
117	loss of rbx1-binding.
129	no effect on activity, when assayed in a sic1-scf-cdc4 ubiquitination assay.
129	complete loss of activity, when assayed in a sic1-scf-cdc4 ubiquitination assay.
133	no effect on activity, when assayed in a sic1-scf-cdc4 ubiquitination assay.
138	decreases monoubiquitination of nfkbia and inhibits polyubiquitination of nfkbia.
143	inhibits polyubiquitination of nfkbia; when associated with a-147; a-149; a-150 and a-153.
147	inhibits polyubiquitination of nfkbia; when associated with a-143; a-149; a-150 and a-153.
149	inhibits polyubiquitination of nfkbia; when associated with a-147; a-147; a-150 and a-153.
150	inhibits polyubiquitination of nfkbia; when associated with a-143; a-147; a-149 and a-153.
153	inhibits polyubiquitination of nfkbia; when associated with a-143; a-147; a-149 and a-150.
203	abolishes phosphorylation by ck2. impairs nuclear localization; when associated with a-222; a-231; a-233 and a-236.
222	abolishes phosphorylation by ck2. impairs nuclear localization; when associated with a-203; a-231; a-233 and a-236.
231	abolishes phosphorylation by ck2. impairs nuclear localization; when associated with a-203; a-222; a-233 and a-236.
233	abolishes phosphorylation by ck2. impairs nuclear localization; when associated with a-203; a-222; a-231 and a-236.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 196 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, WONG_PROTEASOME_GENE_MODULE, GOBP_RESPONSE_TO_INTERFERON_BETA, BLALOCK_ALZHEIMERS_DISEASE_UP, REACTOME_DOWNSTREAM_TCR_SIGNALING, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (10): G1/S transition of mitotic cell cycle (GO:0000082), protein polyubiquitination (GO:0000209), DNA replication initiation (GO:0006270), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), cellular response to interferon-beta (GO:0035458), protein modification process (GO:0036211), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K48-linked ubiquitination (GO:0070936), protein modification by small protein conjugation (GO:0032446)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), ATP binding (GO:0005524), ubiquitin conjugating enzyme activity (GO:0061631), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), ubiquitin-like protein transferase activity (GO:0019787)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), nuclear speck (GO:0016607), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
TCR signaling	1
Fc epsilon receptor (FCERI) signaling	1
C-type lectin receptors (CLRs)	1
Protein ubiquitination	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
DNA metabolic process	1
DNA-templated DNA replication	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
protein metabolic process	1
macromolecule modification	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein polyubiquitination	1
protein modification by small protein conjugation or removal	1
ubiquitin-like protein transferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein conjugating enzyme activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

4176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDC34	SKP1	P34991	997
CDC34	RBX1	P62877	990
CDC34	CUL1	Q13616	968
CDC34	FBXW7	Q969H0	908
CDC34	UBA1	P22314	900
CDC34	BTRC	Q9Y297	847
CDC34	EGLN1	Q9GZT9	806
CDC34	NEDD8	Q15843	781
CDC34	MGRN1	O60291	718
CDC34	FLI1	Q01543	711
CDC34	ATF5	Q9Y2D1	673
CDC34	GLMN	Q92990	668
CDC34	VCP	P55072	643
CDC34	SMURF2	Q9HAU4	643
CDC34	STAMBP	O95630	632
CDC34	UBE2M	P61081	632

IntAct

57 interactions, top by confidence:

A	B	Type	Score
CDC34	BTRC	psi-mi:“MI:0407”(direct interaction)	0.730
CDC34	BTRC	psi-mi:“MI:0915”(physical association)	0.730
CDC34	SDCBP	psi-mi:“MI:0915”(physical association)	0.720
SDCBP	CDC34	psi-mi:“MI:0915”(physical association)	0.720
CDC34		psi-mi:“MI:0195”(covalent binding)	0.680
CDC34		psi-mi:“MI:0407”(direct interaction)	0.680
CDC34	CSNK2B	psi-mi:“MI:0915”(physical association)	0.590
CDC34	CSNK2B	psi-mi:“MI:0407”(direct interaction)	0.590
CDC34	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	CDC34	psi-mi:“MI:0915”(physical association)	0.560
CDC34	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CDC34	MEOX1	psi-mi:“MI:0915”(physical association)	0.560
CUL1	CDC34	psi-mi:“MI:0915”(physical association)	0.540
CUL1	CDC34	psi-mi:“MI:0407”(direct interaction)	0.540
DUSP1	UBB	psi-mi:“MI:0915”(physical association)	0.540
TCEANC2	HTATSF1	psi-mi:“MI:0914”(association)	0.530
CDC34	RBX1	psi-mi:“MI:0407”(direct interaction)	0.440
CDC34	ZNRF1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
STT3B	CDC34	psi-mi:“MI:0915”(physical association)	0.400
CORO7	CDC34	psi-mi:“MI:0915”(physical association)	0.400
CSNK2B	CDC34	psi-mi:“MI:0915”(physical association)	0.370
CDC34	TIMM13	psi-mi:“MI:0915”(physical association)	0.370
EIF3K	CDC34	psi-mi:“MI:0915”(physical association)	0.370
TMEM14C	CDC34	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (506): CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), CDC34 (Affinity Capture-MS), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), SDCBP (Two-hybrid), SIAH1 (Two-hybrid), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex), ING4 (Reconstituted Complex), CDC34 (Reconstituted Complex), CDC34 (Reconstituted Complex)

ESM2 similar proteins: A3KN22, O74549, P0C8G3, P21734, P25869, P27949, P49427, P51965, P52482, P52491, P61081, P61082, P62253, P62254, P62255, Q08BH7, Q1RMW1, Q29503, Q3UWQ3, Q42540, Q42541, Q54TI6, Q55EY8, Q5M8Y2, Q5U203, Q5ZKX6, Q6C9W0, Q6CSW8, Q6DCZ9, Q6FVQ8, Q6IRC7, Q6NY82, Q6P8D9, Q6ZWZ2, Q712K3, Q75AF2, Q7ZY08, Q8CFI2, Q91W82, Q95017

Diamond homologs: A0A1B0GUS4, A5PJC4, A5PKP9, D3ZDK2, O13685, O14933, O74196, O74810, P0C8G3, P0C8G4, P0C8G5, P15731, P15732, P21734, P25867, P25869, P27949, P35128, P35129, P35131, P35132, P35133, P35134, P35135, P43102, P46595, P49427, P51668, P51965, P52482, P52483, P52485, P52487, P52490, P52492, P61077, P61078, P61079, P61080, P61088

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
CSNK2A1	“down-regulates activity”	CDC34	phosphorylation
CSNK2B	unknown	CDC34	phosphorylation
RNF7	“down-regulates activity”	CDC34	polyubiquitination
CDC34	“up-regulates activity”	SCF-betaTRCP	binding
CDC34	“up-regulates activity”	SCF-FBW2	binding
CDC34	“up-regulates activity”	SCF-FBW7	binding
CDC34	“up-regulates activity”	SCF-SKP2	binding
RPS6KA1	“down-regulates quantity by destabilization”	CDC34	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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
Degradation of CRY and PER proteins	5	37.9×	1e-05
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	5	35.2×	2e-05
Regulation of PLK1 Activity at G2/M Transition	5	21.9×	1e-04
Antigen processing: Ubiquitination & Proteasome degradation	8	10.3×	3e-05
Neddylation	5	8.2×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein K48-linked ubiquitination	5	24.1×	4e-04
ubiquitin-dependent protein catabolic process	5	10.6×	2e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	6	8.9×	1e-03
protein ubiquitination	6	7.1×	4e-03
spermatogenesis	6	6.0×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3062384	GRCh37/hg19 19p13.3(chr19:260911-1210337)x1	Pathogenic

SpliceAI

1044 predictions. Top by Δscore:

Variant	Effect	Δscore
19:532105:CAAGG:C	donor_loss	1.0000
19:532106:AAGGT:A	donor_loss	1.0000
19:532110:T:A	donor_loss	1.0000
19:535920:CGAGG:C	donor_loss	1.0000
19:535923:GGT:G	donor_loss	1.0000
19:535924:G:GA	donor_loss	1.0000
19:535925:T:G	donor_loss	1.0000
19:536236:T:A	acceptor_gain	1.0000
19:536237:GTGCA:G	acceptor_loss	1.0000
19:536238:T:TA	acceptor_gain	1.0000
19:536238:TGCAG:T	acceptor_loss	1.0000
19:536239:GCAG:G	acceptor_loss	1.0000
19:536240:CAGA:C	acceptor_loss	1.0000
19:536241:A:AG	acceptor_gain	1.0000
19:536241:AGA:A	acceptor_loss	1.0000
19:536241:AGAC:A	acceptor_gain	1.0000
19:536241:AGACG:A	acceptor_gain	1.0000
19:536242:G:GG	acceptor_gain	1.0000
19:536242:GA:G	acceptor_gain	1.0000
19:536242:GAC:G	acceptor_gain	1.0000
19:536242:GACG:G	acceptor_gain	1.0000
19:536242:GACGG:G	acceptor_gain	1.0000
19:536336:GTCAG:G	donor_gain	1.0000
19:536337:TCAG:T	donor_loss	1.0000
19:536340:GG:G	donor_loss	1.0000
19:536341:G:GG	donor_gain	1.0000
19:536342:T:A	donor_loss	1.0000
19:537011:A:AG	acceptor_gain	1.0000
19:537011:AG:A	acceptor_gain	1.0000
19:537012:G:GG	acceptor_gain	1.0000

AlphaMissense

1544 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:532010:G:A	G27R	1.000
19:532010:G:C	G27R	1.000
19:532011:G:A	G27E	1.000
19:532052:T:A	W41R	1.000
19:532052:T:C	W41R	1.000
19:532065:T:A	I45N	1.000
19:532070:G:A	G47R	1.000
19:532070:G:C	G47R	1.000
19:532070:G:T	G47W	1.000
19:532071:G:A	G47E	1.000
19:532098:G:A	G56D	1.000
19:532104:T:C	F58S	1.000
19:535850:T:C	F64S	1.000
19:535864:C:T	P69S	1.000
19:535865:C:A	P69Q	1.000
19:535877:C:A	P73Q	1.000
19:535888:T:C	F77L	1.000
19:535889:T:C	F77S	1.000
19:535890:C:A	F77L	1.000
19:535890:C:G	F77L	1.000
19:535903:T:A	W82R	1.000
19:535903:T:C	W82R	1.000
19:535906:C:G	H83D	1.000
19:535907:A:G	H83R	1.000
19:535908:C:A	H83Q	1.000
19:535908:C:G	H83Q	1.000
19:535910:C:A	P84H	1.000
19:535910:C:G	P84R	1.000
19:535914:C:A	N85K	1.000
19:535914:C:G	N85K	1.000

dbSNP variants (sampled 300 via entrez): RS1000039836 (19:530009 G>A,C), RS1000261886 (19:534970 C>T), RS1000262892 (19:533890 C>T), RS1000562714 (19:529914 G>A), RS1000593646 (19:534180 G>T), RS1000601098 (19:533651 G>A), RS1000873739 (19:542200 G>A), RS1001007770 (19:533481 C>T), RS1001114980 (19:537437 C>T), RS1001201894 (19:539787 T>C,G), RS1001383918 (19:541736 C>G), RS1001414844 (19:541613 C>G,T), RS1001447436 (19:534857 T>A,C), RS1002130385 (19:533726 A>T), RS1002270328 (19:532202 C>A,T)

Disease associations

OMIM: gene MIM:116948 | 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Acrolein	affects cotreatment, increases oxidation, decreases expression, increases abundance	2
Air Pollutants	affects expression, affects cotreatment, increases abundance, increases oxidation	2
Benzo(a)pyrene	decreases expression	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
cryptolepine	decreases expression	1
ochratoxin A	affects cotreatment, decreases expression	1
cupric chloride	affects expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
U 0126	affects expression, affects reaction	1
2-palmitoylglycerol	increases expression	1
licochalcone B	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	increases expression	1
Sunitinib	increases expression	1
Citrinin	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Environmental Pollutants	affects expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SI03	HAP1 CDC34 (-) 1	Cancer cell line	Male
CVCL_SI04	HAP1 CDC34 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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