WDR76

Summary

WDR76 (WD repeat domain 76, HGNC:25773) is a protein-coding gene on chromosome 15q15.3, encoding WD repeat-containing protein 76 (Q9H967). Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.

Enables enzyme binding activity. Involved in DNA damage response. Located in heterochromatin; nucleus; and site of DNA damage.

Source: NCBI Gene 79968 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 104 total
• MANE Select transcript: NM_024908

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25773
Approved symbol	WDR76
Name	WD repeat domain 76
Location	15q15.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12973, Cmr1
Ensembl gene	ENSG00000092470
Ensembl biotype	protein_coding
OMIM	620302
Entrez	79968

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000263795, ENST00000381246, ENST00000452115, ENST00000478130, ENST00000861438, ENST00000939892, ENST00000939893, ENST00000965236

RefSeq mRNA: 2 — MANE Select: NM_024908 NM_001167941, NM_024908

CCDS: CCDS10106, CCDS53938

Canonical transcript exons

ENST00000263795 — 13 exons

Exon	Start	End
ENSE00000588132	43856946	43857163
ENSE00001182698	43851087	43851245
ENSE00001182703	43843901	43844054
ENSE00001182711	43842415	43842516
ENSE00001182713	43839605	43839728
ENSE00001182714	43836161	43836216
ENSE00001182717	43835061	43835150
ENSE00001182725	43827002	43827092
ENSE00001902553	43866128	43868412
ENSE00003504507	43827965	43828366
ENSE00003523828	43858671	43858823
ENSE00003686416	43861333	43861386
ENSE00003785074	43842628	43842671

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 90.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.2689 / max 252.1585, expressed in 1651 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146357	17.2689	1651

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	90.21	gold quality
ganglionic eminence	UBERON:0004023	89.43	gold quality
ventricular zone	UBERON:0003053	89.40	gold quality
secondary oocyte	CL:0000655	86.99	gold quality
endothelial cell	CL:0000115	84.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.36	gold quality
calcaneal tendon	UBERON:0003701	81.73	gold quality
embryo	UBERON:0000922	81.36	gold quality
cortical plate	UBERON:0005343	80.21	gold quality
bone marrow cell	CL:0002092	78.61	gold quality
bone marrow	UBERON:0002371	78.60	gold quality
stromal cell of endometrium	CL:0002255	77.81	gold quality
lymph node	UBERON:0000029	77.61	gold quality
rectum	UBERON:0001052	76.48	gold quality
body of pancreas	UBERON:0001150	76.34	gold quality
mucosa of transverse colon	UBERON:0004991	75.55	gold quality
vermiform appendix	UBERON:0001154	75.32	gold quality
tendon	UBERON:0000043	74.76	gold quality
colonic epithelium	UBERON:0000397	74.55	gold quality
islet of Langerhans	UBERON:0000006	74.09	gold quality
pancreas	UBERON:0001264	74.09	gold quality
granulocyte	CL:0000094	72.13	gold quality
esophagus mucosa	UBERON:0002469	71.69	gold quality
esophagus	UBERON:0001043	71.28	gold quality
popliteal artery	UBERON:0002250	71.17	gold quality
tibial artery	UBERON:0007610	71.16	gold quality
smooth muscle tissue	UBERON:0001135	70.98	gold quality
lower esophagus	UBERON:0013473	70.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.84	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	263.23
E-MTAB-6075	yes	256.87
E-MTAB-7052	yes	99.61
E-ANND-3	yes	5.70
E-GEOD-110499	no	265.22
E-GEOD-111727	no	187.63
E-MTAB-6911	no	132.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

74 targeting WDR76, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1825	99.72	68.11	1089

Literature-anchored findings (GeneRIF, showing 7)

• To examine the proposition that FLJ12973 is involved in colorectal cancer we analysed 31 tumours for sequence variation. No missense changes or pathogenic mutations–truncating or splice site–were detected in any of the tumours. (PMID:12860291)
• work demonstrates the chromatin and DNA damage protein associations of WDR76 and demonstrates the rapid response of WDR76 to laser induced DNA damage (PMID:27248496)
• Study identifies WD40-repeat protein 76 (WDR76) as one of the HRAS binding proteins using proteomic analyses of hepatocellular carcinomas tissue form human patients and mouse diethylnitrosamine-induced liver carcinogenesis model and demonstrates that WDR76 functions as a tumor suppressor via RAS degradation. (PMID:30655611)
• Biochemical Reduction of the Topology of the Diverse WDR76 Protein Interactome. (PMID:31353912)
• destabilization of RAS by WDR76 is a potential strategy for targeting malignant CRC involving CSC activation (PMID:31362761)
• The role of WDR76 protein in human diseases. (PMID:33714259)
• Kurarinone induced p53-independent G0/G1 cell cycle arrest by degradation of K-RAS via WDR76 in human colorectal cancer cells. (PMID:35381263)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr76	ENSDARG00000053554
mus_musculus	Wdr76	ENSMUSG00000027242
rattus_norvegicus	Wdr76	ENSRNOG00000022491

Protein

Protein identifiers

WD repeat-containing protein 76 — Q9H967 (reviewed: Q9H967)

All UniProt accessions (3): Q9H967, A0A0C4DFX7, C9JE56

UniProt curated annotations — full annotation on UniProt →

Function. Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.

Subunit / interactions. Interacts with CUL4A and/or CUL4B.

Similarity. Belongs to the WD repeat DDB2/WDR76 family.

RefSeq proteins (2): NP_001161413, NP_079184* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR050853	WD_repeat_DNA-damage-binding	Family

Pfam: PF00400

UniProt features (14 total): repeat 7, compositionally biased region 2, sequence variant 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H967-F1	75.24	0.54

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 165 (showing top): GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, FISCHER_G1_S_CELL_CYCLE, GOBP_CELL_CYCLE_PHASE_TRANSITION, MITSIADES_RESPONSE_TO_APLIDIN_DN, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_REGULATION_OF_DNA_DAMAGE_CHECKPOINT

GO Biological Process (2): DNA damage response (GO:0006974), regulation of DNA damage checkpoint (GO:2000001)

GO Molecular Function (3): DNA binding (GO:0003677), enzyme binding (GO:0019899), protein binding (GO:0005515)

GO Cellular Component (3): heterochromatin (GO:0000792), nucleus (GO:0005634), site of DNA damage (GO:0090734)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to stress	1
DNA damage checkpoint signaling	1
regulation of cellular response to stress	1
regulation of cell cycle checkpoint	1
nucleic acid binding	1
protein binding	1
binding	1
chromatin	1
intracellular membrane-bounded organelle	1
chromosome	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1773 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR76	HELLS	Q9NRZ9	869
WDR76	THYN1	Q9P016	766
WDR76	DDB1	Q16531	703
WDR76	CUL4A	Q13619	585
WDR76	CUL4B	Q13620	583
WDR76	GAS2L3	Q86XJ1	574
WDR76	DCAF8	Q5TAQ9	518
WDR76	CBX3	Q13185	515
WDR76	TCP1	P17987	504
WDR76	GINS2	Q9Y248	491
WDR76	CASP8AP2	Q9UKL3	488
WDR76	CHAF1B	Q13112	487
WDR76	BMAL1	O00327	486
WDR76	LONRF1	Q17RB8	456
WDR76	WDR75	Q8IWA0	450

IntAct

63 interactions, top by confidence:

A	B	Type	Score
EZH2	EPOP	psi-mi:“MI:0914”(association)	0.730
CUL4B	CUL4A	psi-mi:“MI:0914”(association)	0.730
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
H2AC4	PPM1G	psi-mi:“MI:0914”(association)	0.670
SPIN1	SPINDOC	psi-mi:“MI:0914”(association)	0.640
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
CAMK2D	ELP1	psi-mi:“MI:0914”(association)	0.530
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
WDR76		psi-mi:“MI:0915”(physical association)	0.400
Cbx1		psi-mi:“MI:0914”(association)	0.350
Atrx	ELOC	psi-mi:“MI:0914”(association)	0.350
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
LCOR		psi-mi:“MI:0914”(association)	0.350
AP4M1		psi-mi:“MI:0914”(association)	0.350
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Eif3i	CBX4	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
ZNRD2	KRBA1	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
CAMK2D	SETD1A	psi-mi:“MI:0914”(association)	0.350
IKZF1	MTA2	psi-mi:“MI:0914”(association)	0.350
WDR76	PARP1	psi-mi:“MI:0914”(association)	0.350
CSNK2B	OSBPL8	psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (735): HELLS (Affinity Capture-MS), SRRM2 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), XRCC6 (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), ZC3HAV1 (Affinity Capture-MS), GNB2L1 (Affinity Capture-MS), SUGT1 (Affinity Capture-MS), RPSA (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), BAG2 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT8 (Affinity Capture-MS), CCT5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KIZ8, A0A1L8GXY4, A0A571BF63, A0A8M9QN10, A2CEI4, A2RRP1, A4D1P6, A6H8T2, A9X1C6, B0FXQ5, B1WC10, B2KIQ4, B2RY71, B2RYI0, B7FF09, B7FF12, E9PYY5, F1QHZ6, Q1LXZ7, Q2HJE1, Q3UMY5, Q402B2, Q4V8G4, Q5R6T6, Q5RE88, Q5U1Z0, Q5VTH9, Q5XIZ9, Q5ZLL7, Q6DFC6, Q6DTM3, Q6GPB9, Q6P2C0, Q6TEN6, Q7TMQ7, Q7ZVR1, Q8BMG7, Q8BX17, Q8C147, Q8IWG1

Diamond homologs: A6PWY4, A9X1C6, B2KIQ4, Q4KLQ5, Q9H967, Q4PGT8, A1DNV8, P0CS56, P0CS57, Q4WLU1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
PRC2 methylates histones and DNA	6	17.6×	5e-04
Defective pyroptosis	5	15.0×	2e-03
Interaction of NuRD complexes with transcription factors	6	14.6×	7e-04
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	5	14.6×	2e-03
NuRD complex assembly	5	13.6×	3e-03
HDACs deacetylate histones	5	11.6×	4e-03
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	5	11.6×	4e-03
Negative Regulation of CDH1 Gene Transcription	5	11.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	87
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2643 predictions. Top by Δscore:

Variant	Effect	Δscore
15:43827092:GGTGA:G	donor_loss	1.0000
15:43827094:T:A	donor_loss	1.0000
15:43835055:TTATA:T	acceptor_loss	1.0000
15:43835057:ATAG:A	acceptor_gain	1.0000
15:43835058:TAG:T	acceptor_loss	1.0000
15:43835059:A:AG	acceptor_gain	1.0000
15:43835059:A:AT	acceptor_loss	1.0000
15:43835059:AG:A	acceptor_gain	1.0000
15:43835060:G:A	acceptor_loss	1.0000
15:43835060:G:GG	acceptor_gain	1.0000
15:43835060:GG:G	acceptor_gain	1.0000
15:43836156:TACA:T	acceptor_loss	1.0000
15:43836158:CAGTC:C	acceptor_loss	1.0000
15:43836159:A:AG	acceptor_gain	1.0000
15:43836159:AGTCT:A	acceptor_gain	1.0000
15:43836160:G:GT	acceptor_gain	1.0000
15:43836160:GT:G	acceptor_gain	1.0000
15:43836160:GTC:G	acceptor_gain	1.0000
15:43836160:GTCT:G	acceptor_gain	1.0000
15:43836160:GTCTG:G	acceptor_gain	1.0000
15:43839602:TAGAA:T	acceptor_loss	1.0000
15:43839603:A:AG	acceptor_gain	1.0000
15:43839603:AGAAA:A	acceptor_loss	1.0000
15:43839604:G:GC	acceptor_loss	1.0000
15:43839604:G:GG	acceptor_gain	1.0000
15:43839604:GAAA:G	acceptor_gain	1.0000
15:43839725:AACT:A	donor_gain	1.0000
15:43839726:ACT:A	donor_gain	1.0000
15:43839727:CT:C	donor_gain	1.0000
15:43839727:CTG:C	donor_loss	1.0000

AlphaMissense

4114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:43866174:T:A	W555R	0.996
15:43866174:T:C	W555R	0.996
15:43851192:A:C	S380R	0.992
15:43851194:C:A	S380R	0.992
15:43851194:C:G	S380R	0.992
15:43851211:G:C	R386P	0.991
15:43866176:G:C	W555C	0.991
15:43866176:G:T	W555C	0.991
15:43835096:A:C	R166S	0.989
15:43835096:A:T	R166S	0.989
15:43858784:G:T	G508V	0.985
15:43866175:G:C	W555S	0.983
15:43851193:G:T	S380I	0.980
15:43858768:T:C	F503L	0.979
15:43858770:T:A	F503L	0.979
15:43858770:T:G	F503L	0.979
15:43858784:G:A	G508D	0.979
15:43861343:A:C	S525R	0.979
15:43861345:C:A	S525R	0.979
15:43861345:C:G	S525R	0.979
15:43835118:G:C	A174P	0.978
15:43851142:T:A	V363D	0.978
15:43858820:T:C	L520P	0.978
15:43835098:T:C	L167P	0.976
15:43858763:C:A	A501D	0.975
15:43866355:G:T	G615V	0.975
15:43857055:G:C	R434P	0.973
15:43835095:G:C	R166T	0.972
15:43844014:C:A	A331E	0.972
15:43858806:T:G	C515W	0.972

dbSNP variants (sampled 300 via entrez): RS1000072302 (15:43843262 C>A), RS1000077066 (15:43866543 T>A), RS1000088675 (15:43836718 G>C), RS1000109411 (15:43852307 C>T), RS1000230889 (15:43849440 G>T), RS1000280224 (15:43849614 C>T), RS1000291176 (15:43861040 C>T), RS1000309862 (15:43861103 A>G,T), RS1000424807 (15:43854708 G>T), RS1000508822 (15:43843501 A>G), RS1000533263 (15:43866792 A>AT), RS1000559752 (15:43855985 A>T), RS1000579622 (15:43848419 A>T), RS1000625626 (15:43862422 A>G), RS1000645725 (15:43860037 G>A)

Disease associations

OMIM: gene MIM:620302 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001699_2	Serum albumin levels	2.000000e-08
GCST004748_31	Lung cancer	3.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
trichostatin A	decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
aminomethylphosphonic acid (AMPA)	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
pentanal	decreases expression	1
phenethyl isothiocyanate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases 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_TX93	HAP1 WDR76 (-) 1	Cancer cell line	Male
CVCL_TX94	HAP1 WDR76 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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