RAD18

Summary

RAD18 (RAD18 E3 ubiquitin protein ligase, HGNC:18278) is a protein-coding gene on chromosome 3p25.3, encoding E3 ubiquitin-protein ligase RAD18 (Q9NS91). E3 ubiquitin-protein ligase involved in postreplication repair of UV-damaged DNA.

The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is an ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring-finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens.

Source: NCBI Gene 56852 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 106 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_020165

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18278
Approved symbol	RAD18
Name	RAD18 E3 ubiquitin protein ligase
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	RNF73
Ensembl gene	ENSG00000070950
Ensembl biotype	protein_coding
OMIM	605256
Entrez	56852

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000264926, ENST00000413832, ENST00000415439, ENST00000418463, ENST00000421052, ENST00000427329, ENST00000429790, ENST00000469793, ENST00000473069, ENST00000495087, ENST00000858877, ENST00000956589

RefSeq mRNA: 1 — MANE Select: NM_020165 NM_020165

CCDS: CCDS2571

Canonical transcript exons

ENST00000264926 — 13 exons

Exon	Start	End
ENSE00000965806	8941467	8941804
ENSE00000965807	8939554	8939653
ENSE00000965808	8935871	8936055
ENSE00000965809	8913644	8913720
ENSE00001077422	8877075	8881459
ENSE00003462847	8963335	8963472
ENSE00003467257	8912312	8912372
ENSE00003469836	8890389	8890451
ENSE00003478111	8947220	8947290
ENSE00003497996	8898894	8899047
ENSE00003606006	8948509	8948570
ENSE00003659516	8958920	8959001
ENSE00003688844	8902380	8902520

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 88.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4599 / max 100.4753, expressed in 1686 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40954	7.8694	1663
40953	1.5905	747

Top tissues by expression

238 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	88.28	gold quality
calcaneal tendon	UBERON:0003701	85.35	gold quality
ventricular zone	UBERON:0003053	83.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.37	gold quality
embryo	UBERON:0000922	82.20	gold quality
ganglionic eminence	UBERON:0004023	82.20	gold quality
tendon	UBERON:0000043	80.59	gold quality
kidney epithelium	UBERON:0004819	78.87	gold quality
adrenal tissue	UBERON:0018303	78.75	gold quality
jejunal mucosa	UBERON:0000399	78.61	gold quality
stromal cell of endometrium	CL:0002255	78.54	gold quality
colonic epithelium	UBERON:0000397	77.47	gold quality
cortical plate	UBERON:0005343	77.42	gold quality
islet of Langerhans	UBERON:0000006	76.92	gold quality
upper arm skin	UBERON:0004263	76.77	gold quality
bone marrow cell	CL:0002092	76.43	gold quality
monocyte	CL:0000576	75.84	gold quality
rectum	UBERON:0001052	75.81	gold quality
leukocyte	CL:0000738	75.70	gold quality
vermiform appendix	UBERON:0001154	75.65	gold quality
tendon of biceps brachii	UBERON:0008188	75.63	silver quality
gall bladder	UBERON:0002110	74.85	gold quality
myocardium	UBERON:0002349	74.47	gold quality
lymph node	UBERON:0000029	74.41	gold quality
bone marrow	UBERON:0002371	74.38	gold quality
duodenum	UBERON:0002114	74.31	gold quality
ileal mucosa	UBERON:0000331	74.23	gold quality
corpus callosum	UBERON:0002336	73.77	gold quality
left ventricle myocardium	UBERON:0006566	73.74	gold quality
secondary oocyte	CL:0000655	73.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F3

miRNA regulators (miRDB)

144 targeting RAD18, 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-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877

Literature-anchored findings (GeneRIF, showing 40)

• hRad18 is a novel interacting partner of HIV-1 integrase; role for post-replication/translesion DNA repair in the retroviral integration process. (PMID:12016221)
• action at DNA replication forks (PMID:12856420)
• Together, our results suggest that MMS-induced accumulation of hRad18 protein at stalled forks involves protein phosphorylation which may be performed by S-phase checkpoint kinases. (PMID:15381075)
• the amount of Rad18 in the nucleus is regulated differentially by mono- and polyubiquitination (PMID:15509568)
• We found that the RAD18 transcript is expressed ubiquitously in various tissues and very highly in the testis in mammals. (PMID:16098139)
• Association of Polkappa with PCNA is regulated by Rad18-mediated PCNA ubiquitination. (PMID:16611994)
• Rad18 is a polypeptide associated with Poleta. The study results suggest that arrested replication forks strengthen interactions among Poleta, Rad18/Rad6 and Rev1, consistent with the requirement for effective TLS by Poleta at sites of DNA lesions. (PMID:16824193)
• RAD18-/- cells were defective in single-strand break repair, but functional for double-strand break repair. (PMID:17158148)
• Higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks. (PMID:17242200)
• WRN functions in a RAD18-dependent damage avoidance pathway. (PMID:17541157)
• RAD18 Arg302Gln polymorphism is associated with non-small-cell lung cancer (PMID:17624554)
• Single nucleotide polymorphism in the RAD18 gene is associated with colorectal cancer (PMID:17914568)
• RAD18 signals DNA polymerase IOTA to stalled replication forks in cells entering S phase with DNA damage. (PMID:18290323)
• The SAP domain of RAD18 (residues 248-282) is crucial for binding of RAD18 complexed with RAD6B to DNA substrates. (PMID:18363965)
• A model in which RAD18 within damage-induced nuclear foci is immobilized and is required for recruitment of Y-family DNA polymerases and subsequent mutagenesis. (PMID:18926833)
• epair of induced and spontaneous DSBs that accumulate RAD18 and RAD51 in G1 phase cells is delayed until S phase. (PMID:19013543)
• Data indicate RAD18 as a key factor that orchestrates HRR through surveillance of the DNA damage signal. (PMID:19396164)
• Hydroquinone could upregulate the expression of Rad18 in L-02 hepatic cells. (PMID:19493487)
• Data show that that WRNIP1 interacts physically with RAD18 and interferes with the binding of RAD18 to forked DNA and to template/primer DNA. (PMID:19556710)
• there is no relation between Rad18 SNP and lung cancer development. (PMID:19630985)
• RAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger (PMID:20385554)
• Rad18 promotes FA core complex-dependent FANCD2 ubiquitination in a manner that is secondary to PCNA mono-ubiquitination. (PMID:20675655)
• RAD18-mediated PCNA monoubiquitination is a central hub for the mobilization of the Fanconi anemia DNA repair network pathway. (PMID:20937699)
• showed that the function of FA signaling pathway is at least partly mediated through coupling with hRad6/hRad18 signaling (HHR6 pathway) (PMID:20967207)
• These data suggest a key role for the E3 ligase activity of RAD18 in the recruitment of FANCD2 and FANCI to chromatin and the events leading to their ubiquitylation during S phase. (PMID:21355096)
• E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6. (PMID:21422291)
• A novel pathway of Rad18-dependent DSB repair that is dissociable from known Rad18-mediated DNA repair mechanisms based on its independence from PCNA ubiquitination and requirement for E3 ligase activity. (PMID:21478670)
• Data show that the homodimeric Rad18 RING domain can recruit two Rad6b E2 enzymes, whereas the full-length Rad18 homodimer binds only to a single Rad6b molecule. (PMID:21549715)
• Data indicate that association of RAD18 with DSBs through ubiquitylated H2A and other ubiquitylated chromatin components allows recruitment of RAD9. (PMID:21858012)
• The results demonstrate that RAD6A and RAD18 form a ternary complex, RAD6A-(RAD18)(2) and the presence of only one RAD6-binding domain in the two RAD18 subunits is sufficient for ternary complex formation and the ligase activity. (PMID:21967848)
• RAD18 interacts with BRCTx in a phosphorylation-dependent manner (PMID:22036607)
• Rad18 is involved in the regulation of melanoma cell proliferation. (PMID:22145991)
• E2F3 controls the ubiquitination of PCNA through the transcriptional regulation of Rad18. (PMID:22391204)
• Ser409, located within the pol-eta binding domain of Rad18, is phosphorylated by c-jun kinase in response to dna damage, promoting the interaction between Rad18 and pol-eta. (PMID:22456510)
• The Rad6-Rad18 enzyme plays an essential role in promoting replication through DNA lesions by translesion synthesis in mammalian cells. (PMID:22547805)
• RNF168, its paralog RNF169, RAD18, and the BRCA1-interacting RAP80 protein accumulate at DNA double strand break sites through the use of bipartite modules composed of ubiquitin binding sites. (PMID:22742833)
• Rad18 plays distinct roles in protecting the genome from oxidative DNA damage in different cell cycle stages. (PMID:23295675)
• Rad18 is targeted to PCNA by DNA polymerase eta. (PMID:23345618)
• Non-canonical CRL4A/4B(CDT2) interacts with RAD18 to modulate post replication repair and cell survival. (PMID:23555860)
• HHR6 and hRad18 can monoubiquitinate FANCD2 at lysine 561 in vitro. This activity may represent a novel stress response pathway. (PMID:24036990)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rad18	ENSDARG00000027938
mus_musculus	Rad18	ENSMUSG00000030254
rattus_norvegicus	Rad18	ENSRNOG00000005907

Protein

Protein identifiers

E3 ubiquitin-protein ligase RAD18 — Q9NS91 (reviewed: Q9NS91)

Alternative names: Postreplication repair protein RAD18, RING finger protein 73, RING-type E3 ubiquitin transferase RAD18

All UniProt accessions (7): Q9NS91, C9J0Q4, F8WAZ7, F8WE49, F8WFA6, H7C0A5, H7C3I2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in postreplication repair of UV-damaged DNA. Postreplication repair functions in gap-filling of a daughter strand on replication of damaged DNA. Associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on ‘Lys-164’. Has ssDNA binding activity.

Subunit / interactions. Homodimer. Interacts with UBE2A and UBE2B, one homodimer binding one molecule of UBE2B. Interacts with SHPRH. Interacts with HLTF. Interacts with SPRTN; leading to enhance chromatin association of RAD18 and RAD18-mediated PCNA ubiquitination and translesion DNA synthesis. Interacts (via C-terminus and phosphorylated form) with SLF1 (via BRCT domains); this interaction is required for efficient repair of UV-induced DNA damage. Interacts with SLF2. Interacts with SMC5; this interaction is increased in a SLF1 or SLF2-dependent manner. Interacts with DNA damage up-regulated protein DDUP. Forms a complex with DDUP and H2AX following DDUP phosphorylation.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RAD18 family.

RefSeq proteins (1): NP_064550* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR003034	SAP_dom	Domain
IPR006642	Rad18_UBZ4	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR039577	Rad18	Family

Pfam: PF02037, PF13923

UniProt features (54 total): modified residue 12, helix 10, strand 5, binding site 4, turn 4, sequence variant 3, mutagenesis site 3, region of interest 3, zinc finger region 2, sequence conflict 2, compositionally biased region 2, chain 1, domain 1, cross-link 1, short sequence motif 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8IR4	X-RAY DIFFRACTION	1.62
8IR2	X-RAY DIFFRACTION	1.75
2Y43	X-RAY DIFFRACTION	1.8
2YBF	X-RAY DIFFRACTION	2
9BD3	X-RAY DIFFRACTION	2.58
2MRE	SOLUTION NMR
2MRF	SOLUTION NMR
5VF0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NS91-F1	67.69	0.35

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): 204; 207; 219; 223

Post-translational modifications (13): 1, 99, 103, 118, 122, 125, 142, 158, 164, 322, 471, 483, 376

Mutagenesis-validated functional residues (3):

Position	Phenotype
27	lower activity toward pcna monoubiquitination.
442	does not interact with slf1 and is defective in restoring cell survival after dna damage; when associated with a-444.
444	does not interact with slf1 and is defective in restoring cell survival after dna damage; when associated with a-442.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins

MSigDB gene sets: 176 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_DNA_DAMAGE_TOLERANCE, KAUFFMANN_DNA_REPAIR_GENES, GOCC_MICROTUBULE_ORGANIZING_CENTER, NFKB_C, GOBP_REGULATION_OF_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_PROTEIN_AUTOUBIQUITINATION, GOCC_CENTROSOME, GOBP_POSITIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_PROTEIN_MONOUBIQUITINATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (7): DNA repair (GO:0006281), DNA damage tolerance (GO:0006301), protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), protein autoubiquitination (GO:0051865), positive regulation of chromosome segregation (GO:0051984), protein ubiquitination (GO:0016567)

GO Molecular Function (13): Y-form DNA binding (GO:0000403), damaged DNA binding (GO:0003684), single-stranded DNA binding (GO:0003697), zinc ion binding (GO:0008270), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), ubiquitin protein ligase activity (GO:0061630), DNA binding (GO:0003677), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), centrosome (GO:0005813), nuclear body (GO:0016604), site of double-strand break (GO:0035861), nuclear inclusion body (GO:0042405), Rad6-Rad18 complex (GO:0097505), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
DNA Damage Bypass	1
Protein ubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membraneless organelle	3
DNA metabolic process	2
DNA damage response	2
protein ubiquitination	2
DNA binding	2
binding	2
DNA replication	1
cellular response to stress	1
chromosome segregation	1
regulation of chromosome segregation	1
positive regulation of cell cycle process	1
protein modification by small protein conjugation	1
DNA secondary structure binding	1
transition metal ion binding	1
modification-dependent protein binding	1
ubiquitin-like protein ligase binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
nucleic acid binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
chromosome	1
centriole	1
microtubule organizing center	1
nucleoplasm	1
site of DNA damage	1
nucleus	1
inclusion body	1
ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2392 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAD18	UBE2A	P49459	987
RAD18	UBE2V2	Q15819	983
RAD18	UBE2B	P23567	977
RAD18	UBE2N	P61088	970
RAD18	SHPRH	Q149N8	969
RAD18	RAD52	P43351	958
RAD18	HLTF	Q14527	952
RAD18	RAD51C	O43502	942
RAD18	RAD51	Q06609	934
RAD18	SMC5	Q8IY18	924
RAD18	POLL	Q9UGP5	916
RAD18	UBE2I	P50550	850
RAD18	REV1	Q9UBZ9	846
RAD18	REV3L	O60673	846
RAD18	RNF168	Q8IYW5	845

IntAct

149 interactions, top by confidence:

A	B	Type	Score
ATF2	JUN	psi-mi:“MI:0914”(association)	0.950
LLGL2	PRKCI	psi-mi:“MI:0914”(association)	0.890
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
UBE2B	RAD18	psi-mi:“MI:0407”(direct interaction)	0.840
RAD18	UBE2B	psi-mi:“MI:0915”(physical association)	0.840
MAGEA4	RAD18	psi-mi:“MI:0915”(physical association)	0.800
SRP9	SRP72	psi-mi:“MI:0914”(association)	0.730
TAX1BP1	RAD18	psi-mi:“MI:0915”(physical association)	0.720
RAD18	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.720
HLTF	UBE2N	psi-mi:“MI:0914”(association)	0.680
UBE2A	RAD18	psi-mi:“MI:0915”(physical association)	0.660
LLGL1	DNAJA2	psi-mi:“MI:0914”(association)	0.640
RAD18	HLTF	psi-mi:“MI:0915”(physical association)	0.620
HLTF	PCNA	psi-mi:“MI:0914”(association)	0.560
GOLGA2	RAD18	psi-mi:“MI:0915”(physical association)	0.560
ORC2	RAD18	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	RAD18	psi-mi:“MI:0915”(physical association)	0.560
PDCD5	RAD18	psi-mi:“MI:0915”(physical association)	0.560
ARRDC3	RAD18	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	RAD18	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	RAD18	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (717): UBC (Co-crystal Structure), UBC (Reconstituted Complex), RAD18 (Two-hybrid), RAD18 (Affinity Capture-Western), RAD18 (Affinity Capture-MS), RAD18 (Affinity Capture-MS), PCNA (Biochemical Activity), UBE2A (Reconstituted Complex), RAD18 (Biochemical Activity), RAD18 (Reconstituted Complex), UBC (Reconstituted Complex), UBC (Reconstituted Complex), RAD18 (Biochemical Activity), UBC (Reconstituted Complex), RAD18 (Affinity Capture-MS)

ESM2 similar proteins: A2AJT4, A2CG63, B0S733, F1QNX7, G3V8T1, O75376, O94988, P29536, Q02040, Q14241, Q149C2, Q15695, Q15696, Q28G87, Q2KIC0, Q4FZU3, Q4G0J3, Q4KKX4, Q4LE39, Q4R627, Q53F19, Q561R3, Q5NCR9, Q5R4U2, Q5RL73, Q5U2T3, Q5XIN3, Q5ZM19, Q60974, Q62377, Q63187, Q64707, Q6PFK1, Q6PGZ3, Q8BZR9, Q8C761, Q8CB77, Q8K2X2, Q8QG78, Q8TDR0

Diamond homologs: A0JN86, B3DK16, D3YY23, P23798, P25172, P25916, P29128, P29836, P35226, P35227, P35820, Q03605, Q07G17, Q09268, Q17RB8, Q1JPS1, Q28H21, Q2KJ29, Q2YDF9, Q32KX7, Q3KNV8, Q3UK78, Q4QR06, Q5R8L2, Q5SDR3, Q5XI70, Q640D5, Q6DLV9, Q7T3E6, Q7ZYZ7, Q86SE9, Q8BGI1, Q8BTQ0, Q8JIR0, Q8R023, Q91648, Q94AY3, Q99NA9, Q9BSM1, Q9BYE7

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CDC7	unknown	RAD18	phosphorylation
RNF8	up-regulates	RAD18	binding
RAD18	up-regulates	PCNA	ubiquitination
Ub:E2	“up-regulates activity”	RAD18	ubiquitination
RAD18	“up-regulates activity”	TP53BP1	ubiquitination
RAD18	“up-regulates activity”	PCNA	ubiquitination
RAD18	“up-regulates activity”	FANCD2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
E3 ubiquitin ligases ubiquitinate target proteins	6	12.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	5	13.1×	3e-03
double-strand break repair via homologous recombination	8	10.1×	5e-04
DNA damage response	12	5.2×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2389 predictions. Top by Δscore:

Variant	Effect	Δscore
3:8881370:CG:C	donor_gain	1.0000
3:8898888:TCTTA:T	donor_loss	1.0000
3:8898889:CTTAC:C	donor_loss	1.0000
3:8898890:TTA:T	donor_loss	1.0000
3:8898891:TA:T	donor_loss	1.0000
3:8898892:A:AC	donor_gain	1.0000
3:8898892:A:AT	donor_loss	1.0000
3:8898893:C:CC	donor_gain	1.0000
3:8912310:A:AC	donor_gain	1.0000
3:8912311:C:CC	donor_gain	1.0000
3:8912311:CGATA:C	donor_gain	1.0000
3:8913642:A:AC	donor_gain	1.0000
3:8913643:C:CC	donor_gain	1.0000
3:8913643:CA:C	donor_gain	1.0000
3:8913648:T:A	donor_gain	1.0000
3:8939650:TCCA:T	acceptor_gain	1.0000
3:8939651:CCA:C	acceptor_gain	1.0000
3:8939651:CCAC:C	acceptor_gain	1.0000
3:8939652:CAC:C	acceptor_gain	1.0000
3:8939654:C:CC	acceptor_gain	1.0000
3:8939661:T:C	acceptor_gain	1.0000
3:8939663:T:C	acceptor_gain	1.0000
3:8939663:T:TC	acceptor_gain	1.0000
3:8941806:T:C	acceptor_gain	1.0000
3:8947287:CAGT:C	acceptor_gain	1.0000
3:8947289:GT:G	acceptor_gain	1.0000
3:8947290:TC:T	acceptor_loss	1.0000
3:8947291:C:CC	acceptor_gain	1.0000
3:8947291:C:T	acceptor_loss	1.0000
3:8948567:CAGT:C	acceptor_gain	1.0000

AlphaMissense

3282 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:8948526:A:G	C60R	1.000
3:8935901:C:G	A287P	0.999
3:8948525:C:G	C60S	0.999
3:8948526:A:T	C60S	0.999
3:8948559:A:G	C49R	0.999
3:8958932:A:G	C41R	0.999
3:8958980:A:G	C25R	0.999
3:8948517:A:G	C63R	0.998
3:8948524:A:C	C60W	0.998
3:8948551:T:A	R51S	0.998
3:8948551:T:G	R51S	0.998
3:8948557:A:C	C49W	0.998
3:8948558:C:G	C49S	0.998
3:8948559:A:T	C49S	0.998
3:8948566:G:C	C46W	0.998
3:8948568:A:G	C46R	0.998
3:8958931:C:G	C41S	0.998
3:8958932:A:T	C41S	0.998
3:8958971:A:G	C28R	0.998
3:8958979:C:G	C25S	0.998
3:8958980:A:T	C25S	0.998
3:8935966:A:G	L265S	0.997
3:8935981:A:G	L260P	0.997
3:8939648:A:G	C204R	0.997
3:8947261:G:C	N75K	0.997
3:8947261:G:T	N75K	0.997
3:8947271:A:G	L72P	0.997
3:8948515:G:C	C63W	0.997
3:8948552:C:G	R51T	0.997
3:8948555:A:T	I50K	0.997

dbSNP variants (sampled 300 via entrez): RS1000005765 (3:8922830 C>A,T), RS1000020228 (3:8918918 T>C), RS1000051952 (3:8877965 A>G), RS1000058482 (3:8935090 G>A), RS1000079227 (3:8883738 A>G,T), RS1000114650 (3:8938120 G>A,C), RS1000146408 (3:8922612 T>A), RS1000156844 (3:8954990 C>T), RS1000177085 (3:8944042 G>T), RS1000205054 (3:8894505 A>G), RS1000300615 (3:8890346 T>A,C), RS1000338042 (3:8944682 G>A), RS1000358625 (3:8896145 G>T), RS1000374684 (3:8944322 T>C,G), RS1000389560 (3:8895890 C>T)

Disease associations

OMIM: gene MIM:605256 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004264_4	Clopidogrel active metabolite levels	3.000000e-11
GCST006914_14	Sleep duration	3.000000e-08
GCST007565_104	Morning person	6.000000e-15
GCST007576_300	Chronotype	6.000000e-15
GCST009208_1	Transverse temporal cortex volume	8.000000e-06
GCST009391_181	Metabolite levels	8.000000e-06
GCST012048_7	Triglyceride levels	5.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007966	clopidogrel metabolite measurement
EFO:0008328	chronotype measurement
EFO:0010476	dimethylglycine measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725157 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs187941554	RAD18		0.00	0

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	IC50	330	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178914: Inhibition of RAD18 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.3300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
4-biphenylamine	decreases expression, decreases reaction	2
sodium arsenite	decreases ubiquitination, affects methylation, affects binding, decreases reaction, affects localization	2
Benzo(a)pyrene	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	decreases expression	2
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
pradimicin-IRD	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
terbufos	affects cotreatment, increases expression, decreases expression	1
trichostatin A	decreases expression	1
gossypol acetic acid	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases ubiquitination	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
brevetoxin 2	increases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Acetylcysteine	decreases expression, decreases reaction	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Coumestrol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression, affects expression, affects response to substance	1
Fenthion	affects cotreatment, increases expression, decreases expression	1
Chlordecone	affects binding, decreases reaction	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697644	Binding	Inhibition of RAD18 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1Q98	H414-RAD18(+/-)	Cancer cell line	Male
CVCL_1Q99	H414-RAD18(-/-)	Cancer cell line	Male
CVCL_1R08	HCT116-RAD18(+/-)	Cancer cell line	Male
CVCL_1R09	HCT116-RAD18(-/-)	Cancer cell line	Male
CVCL_E2ID	HAP1 RAD18 (-) 1	Cancer cell line	Male
CVCL_E2IE	HAP1 RAD18 (-) 2	Cancer cell line	Male
CVCL_E2IF	HAP1 RAD18 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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