POLE4

Summary

POLE4 (DNA polymerase epsilon 4, accessory subunit, HGNC:18755) is a protein-coding gene on chromosome 2p12, encoding DNA polymerase epsilon subunit 4 (Q9NR33). Accessory component of the DNA polymerase epsilon complex.

POLE4 is a histone-fold protein that interacts with other histone-fold proteins to bind DNA in a sequence-independent manner. These histone-fold protein dimers combine within larger enzymatic complexes for DNA transcription, replication, and packaging.

Source: NCBI Gene 56655 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_019896

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18755
Approved symbol	POLE4
Name	DNA polymerase epsilon 4, accessory subunit
Location	2p12
Locus type	gene with protein product
Status	Approved
Aliases	p12
Ensembl gene	ENSG00000115350
Ensembl biotype	protein_coding
OMIM	607269
Entrez	56655

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding_CDS_not_defined, 3 protein_coding, 2 retained_intron

ENST00000233699, ENST00000459636, ENST00000465242, ENST00000473023, ENST00000483063, ENST00000485527, ENST00000871512, ENST00000871513

RefSeq mRNA: 1 — MANE Select: NM_019896 NM_019896

CCDS: CCDS1957

Canonical transcript exons

ENST00000483063 — 4 exons

Exon	Start	End
ENSE00001865954	74958643	74958892
ENSE00001943220	74969409	74970128
ENSE00003643749	74959341	74959425
ENSE00003691649	74960105	74960146

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 97.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.4107 / max 267.6987, expressed in 1821 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21085	36.4107	1821

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.55	gold quality
anterior cingulate cortex	UBERON:0009835	96.92	gold quality
mucosa of transverse colon	UBERON:0004991	96.76	gold quality
right adrenal gland cortex	UBERON:0035827	96.48	gold quality
leukocyte	CL:0000738	96.46	gold quality
right adrenal gland	UBERON:0001233	96.46	gold quality
popliteal artery	UBERON:0002250	96.38	gold quality
tibial artery	UBERON:0007610	96.38	gold quality
monocyte	CL:0000576	96.34	gold quality
left adrenal gland	UBERON:0001234	96.23	gold quality
gastrocnemius	UBERON:0001388	96.23	gold quality
left coronary artery	UBERON:0001626	96.09	gold quality
left adrenal gland cortex	UBERON:0035825	96.06	gold quality
aorta	UBERON:0000947	96.01	gold quality
omental fat pad	UBERON:0010414	95.99	gold quality
apex of heart	UBERON:0002098	95.96	gold quality
peritoneum	UBERON:0002358	95.94	gold quality
prefrontal cortex	UBERON:0000451	95.86	gold quality
amygdala	UBERON:0001876	95.85	gold quality
ascending aorta	UBERON:0001496	95.83	gold quality
thoracic aorta	UBERON:0001515	95.83	gold quality
right coronary artery	UBERON:0001625	95.81	gold quality
endocervix	UBERON:0000458	95.71	gold quality
muscle of leg	UBERON:0001383	95.69	gold quality
caudate nucleus	UBERON:0001873	95.69	gold quality
descending thoracic aorta	UBERON:0002345	95.67	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.23	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.21
E-MTAB-7606	no	452.10
E-CURD-114	no	21.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting POLE4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-610	96.84	67.98	905
HSA-MIR-6891-3P	95.80	65.76	683
HSA-MIR-3200-3P	95.41	64.23	396

Literature-anchored findings (GeneRIF, showing 2)

• iochemical analyses establish that POLE3-POLE4 is a histone chaperone that promotes tetrasome formation and DNA supercoiling in vitro. In cells, POLE3-POLE4 binds both newly synthesized and parental histones, and its depletion hinders helicase unwinding and chromatin PCNA unloading and compromises coordinated parental histone retention and new histone deposition (PMID:30217558)
• Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors. (PMID:38753485)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pole4	ENSDARG00000013016
mus_musculus	Pole4	ENSMUSG00000030042
rattus_norvegicus	Pole4	ENSRNOG00000006102
drosophila_melanogaster	PolE4	FBGN0034726
caenorhabditis_elegans		WBGENE00013150

Paralogs (2): NFYC (ENSG00000066136), DRAP1 (ENSG00000175550)

Protein

Protein identifiers

DNA polymerase epsilon subunit 4 — Q9NR33 (reviewed: Q9NR33)

Alternative names: DNA polymerase II subunit 4, DNA polymerase epsilon subunit p12

All UniProt accessions (1): Q9NR33

UniProt curated annotations — full annotation on UniProt →

Function. Accessory component of the DNA polymerase epsilon complex. Participates in DNA repair and in chromosomal DNA replication.

Subunit / interactions. Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interaction with POLE3 is a prerequisite for further binding with POLE and POLE2.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_063949* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003958	CBFA_NFYB_domain	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR050568	Transcr_DNA_Rep_Reg	Family

Pfam: PF00808

Enzyme classification (BRENDA):

• EC 2.7.7.7 — DNA-directed DNA polymerase (BRENDA: 139 organisms, 372 substrates, 325 inhibitors, 281 Km, 239 kcat entries)

Substrate kinetics (BRENDA)

52 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DATP	0.0003–3.2	52
DCTP	0.0001–2.5	46
DTTP	0.0003–47.4	46
DGTP	0.0002–2.5	29
DEOXYNUCLEOSIDE TRIPHOSPHATE	0.0012–0.64	12
DNAN	—	7
7-DEAZA-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.0011–0.344	5
N1-METHYL-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.223–0.403	5
2-AMINOPURINE-2’-DEOXY-D-RIBOSE 5’-TRIPHOSPHATE	0.006–0.0144	2
2-THIO-DCTP	0.067–0.98	2
5-METHYL-DCTP	0.013–1.22	2
DAMP:DG	1.153–1.42	2
DCMP:DG	—	2
DGMP:DG	0.263–0.3511	2
DTMP:DG	1.26–1.43	2

UniProt features (8 total): modified residue 3, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR33-F1	82.79	0.69

Functional residue map

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

Post-translational modifications (3): 2, 11, 25

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-68952	DNA replication initiation
R-HSA-68962	Activation of the pre-replicative complex

MSigDB gene sets: 178 (showing top): E2F_Q4, REACTOME_DNA_REPLICATION, E2F_Q4_01, E2F4DP1_01, KAUFFMANN_DNA_REPAIR_GENES, WEI_MYCN_TARGETS_WITH_E_BOX, E2F1DP1_01, E2F1DP2_01, GOMF_DNA_POLYMERASE_ACTIVITY, GOBP_DNA_BIOSYNTHETIC_PROCESS, KEGG_PURINE_METABOLISM, chr2p12, E2F1_Q3, REACTOME_DNA_REPAIR, LINDVALL_IMMORTALIZED_BY_TERT_UP

GO Biological Process (2): DNA-templated DNA replication (GO:0006261), DNA biosynthetic process (GO:0071897)

GO Molecular Function (4): DNA binding (GO:0003677), DNA-directed DNA polymerase activity (GO:0003887), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), epsilon DNA polymerase complex (GO:0008622), ATAC complex (GO:0140672)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
DNA Damage Bypass	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Synthesis of DNA	1
DNA Replication Pre-Initiation	1
G1/S Transition	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA replication	1
DNA metabolic process	1
nucleic acid biosynthetic process	1
nucleic acid binding	1
DNA polymerase activity	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear chromosome	1
DNA polymerase complex	1
nuclear protein-containing complex	1
SAGA-type complex	1

Protein interactions and networks

STRING

1200 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLE4	POLE3	Q9NRF9	998
POLE4	POLE2	P56282	988
POLE4	POLE	Q07864	964
POLE4	POLD2	P49005	757
POLE4	MBIP	Q9NS73	727
POLE4	TADA2A	O75478	683
POLE4	POLA2	Q14181	634
POLE4	BAZ1A	Q9NRL2	596
POLE4	POLA1	P09884	591
POLE4	YEATS2	Q9ULM3	590
POLE4	POLD1	P28340	567
POLE4	DR1	Q01658	559
POLE4	SGF29	Q96ES7	537
POLE4	CDC45	O75419	529
POLE4	SMARCA5	O60264	527

IntAct

44 interactions, top by confidence:

A	B	Type	Score
POLE2	POLE	psi-mi:“MI:0914”(association)	0.860
POLE4	POLE3	psi-mi:“MI:0915”(physical association)	0.770
POLE4	NFYB	psi-mi:“MI:0915”(physical association)	0.720
NFYB	POLE4	psi-mi:“MI:0915”(physical association)	0.720
POLE3	POLE2	psi-mi:“MI:0914”(association)	0.690
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
POLE2	POLE4	psi-mi:“MI:0914”(association)	0.640
POLE2	CYP4F12	psi-mi:“MI:0914”(association)	0.560
PRKAR1B	POLE4	psi-mi:“MI:0915”(physical association)	0.560
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
HSPA13	POLE4	psi-mi:“MI:0915”(physical association)	0.550
FXYD1	GCHFR	psi-mi:“MI:0914”(association)	0.530
LIN7B	CASK	psi-mi:“MI:0914”(association)	0.530
GALNS	CLGN	psi-mi:“MI:0914”(association)	0.530
POLE3	SMARCA5	psi-mi:“MI:0914”(association)	0.530
POLE4	POLE	psi-mi:“MI:0914”(association)	0.530
POLE	POLE4	psi-mi:“MI:0914”(association)	0.530
POLE4	ORF	psi-mi:“MI:0915”(physical association)	0.500
POLE4	E7	psi-mi:“MI:0915”(physical association)	0.370
UBE3A	POLE4	psi-mi:“MI:0915”(physical association)	0.370
RPS27	POTEF	psi-mi:“MI:0914”(association)	0.350
QTRT1	APBB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (52): POLE4 (Two-hybrid), POLE4 (Affinity Capture-MS), ISY1-RAB43 (Co-fractionation), ISY1 (Co-fractionation), POLE (Co-fractionation), POLE3 (Co-fractionation), POLE4 (Co-fractionation), POLE4 (Two-hybrid), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS), POLE4 (Affinity Capture-MS)

ESM2 similar proteins: A0JPP1, A1A4I4, A1A5B6, A4K436, A6QQ14, A6QQ47, C5IJB0, E1BSW7, O00459, O04173, O08908, O14908, O35465, P23726, P70268, Q12962, Q14318, Q14657, Q14919, Q16512, Q17QX2, Q1JQD7, Q32NY4, Q3B7U9, Q3MII6, Q3V1H9, Q496Y0, Q4R4E4, Q5C9Z4, Q5RE34, Q5XIU9, Q5ZIW1, Q63433, Q63788, Q6K461, Q6PZ03, Q6ZT62, Q7Z6J2, Q8CFK2, Q8HXH0

Diamond homologs: A0JPP1, A6BLW4, A6QQ14, B0XTT5, C6Y4D0, P40096, P70353, Q02516, Q10315, Q13952, Q14919, Q2YDP3, Q4PSE2, Q4X095, Q54DA1, Q58CM8, Q5E9X1, Q5RA23, Q62725, Q655V5, Q6C6M5, Q8L4B2, Q8LCG7, Q9CQ36, Q9D6N5, Q9FGP6, Q9FMV5, Q9NR33, Q9SMP0, Q9XE33, Q9ZVL3, O17072, P79007, Q557I1, Q6BX14, Q6CLM5, Q9FGP7, Q9FGP8, Q9JKP8, Q9NRG0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLE4	“form complex”	“DNA polymerase epsilon”	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

576 predictions. Top by Δscore:

Variant	Effect	Δscore
2:74958863:G:GT	donor_gain	1.0000
2:74958919:G:GT	donor_gain	1.0000
2:74959393:G:T	donor_gain	1.0000
2:74959400:G:GT	donor_gain	1.0000
2:74959401:A:T	donor_gain	1.0000
2:74959416:A:T	donor_gain	1.0000
2:74960147:G:GC	donor_loss	1.0000
2:74960148:T:G	donor_loss	1.0000
2:74958702:G:GT	donor_gain	0.9900
2:74958864:A:T	donor_gain	0.9900
2:74958890:GCG:G	donor_gain	0.9900
2:74958911:GGCA:G	donor_gain	0.9900
2:74958919:G:T	donor_gain	0.9900
2:74958928:G:GT	donor_gain	0.9900
2:74958928:G:T	donor_gain	0.9900
2:74959461:G:GT	donor_gain	0.9900
2:74959462:G:T	donor_gain	0.9900
2:74960103:A:AG	acceptor_gain	0.9900
2:74960104:G:GG	acceptor_gain	0.9900
2:74960149:GAGT:G	donor_loss	0.9900
2:74958893:G:GC	donor_loss	0.9800
2:74958893:G:GG	donor_gain	0.9800
2:74958894:T:TC	donor_loss	0.9800
2:74959392:G:GT	donor_gain	0.9800
2:74959415:G:GT	donor_gain	0.9800
2:74959569:G:GT	donor_gain	0.9800
2:74960098:GTTTC:G	acceptor_loss	0.9800
2:74960099:TTTCA:T	acceptor_loss	0.9800
2:74960100:TTCA:T	acceptor_loss	0.9800
2:74960101:TCA:T	acceptor_loss	0.9800

AlphaMissense

736 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:74960137:T:C	F111L	1.000
2:74960139:T:A	F111L	1.000
2:74960139:T:G	F111L	1.000
2:74958820:G:C	K47N	0.999
2:74958820:G:T	K47N	0.999
2:74959362:G:C	A79P	0.999
2:74959371:G:C	A82P	0.999
2:74959372:C:A	A82D	0.999
2:74959399:G:T	R91M	0.999
2:74959400:G:C	R91S	0.999
2:74959400:G:T	R91S	0.999
2:74959408:T:A	L94H	0.999
2:74960138:T:C	F111S	0.999
2:74960138:T:G	F111C	0.999
2:74960141:T:C	L112P	0.999
2:74958887:G:C	A70P	0.998
2:74958888:C:A	A70D	0.998
2:74959348:T:C	F74S	0.998
2:74959360:T:A	I78N	0.998
2:74959363:C:A	A79E	0.998
2:74959384:C:A	A86D	0.998
2:74959399:G:C	R91T	0.998
2:74959420:A:C	D98A	0.998
2:74959420:A:G	D98G	0.998
2:74959420:A:T	D98V	0.998
2:74960110:G:C	A102P	0.998
2:74960141:T:A	L112Q	0.998
2:74958801:T:C	L41S	0.997
2:74958818:A:G	K47E	0.997
2:74958832:G:C	K51N	0.997

dbSNP variants (sampled 300 via entrez): RS1000051384 (2:74965735 A>G,T), RS1000077043 (2:74963542 C>T), RS1000103146 (2:74965389 G>A), RS1000261381 (2:74963681 G>A), RS1000272127 (2:74969548 A>C,G,T), RS1000287355 (2:74959986 A>G,T), RS1000498076 (2:74961068 C>T), RS1000503525 (2:74967123 T>C), RS1000575418 (2:74959738 G>A), RS1000656380 (2:74961261 C>A), RS1000929252 (2:74959236 C>A,T), RS1001393296 (2:74966140 A>G), RS1001491089 (2:74964636 G>A,T), RS1001720020 (2:74965845 A>C), RS1001959443 (2:74960681 G>A)

Disease associations

OMIM: gene MIM:607269 | 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
GCST011359_12	Venous thromboembolism	5.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression, affects expression	6
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
coumarin	decreases phosphorylation	1
4-phenylbutyric acid	decreases expression	1
entinostat	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydralazine	increases expression, affects cotreatment	1
Progesterone	decreases expression	1
Thimerosal	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Copper Sulfate	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_B2BF	Abcam HeLa POLE4 KO	Cancer cell line	Female
CVCL_TE95	HAP1 POLE4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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