POLE2

Summary

POLE2 (DNA polymerase epsilon 2, accessory subunit, HGNC:9178) is a protein-coding gene on chromosome 14q21.3, encoding DNA polymerase epsilon subunit 2 (P56282). Accessory component of the DNA polymerase epsilon complex. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

DNA polymerase epsilon, which is involved in DNA repair and replication, is composed of a large catalytic subunit and a small accessory subunit. The protein encoded by this gene represents the small subunit (B). Defects in this gene have been linked to colorectal cancer and to combined immunodeficiency.

Source: NCBI Gene 5427 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to POLE2 deficiency (Limited, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 477 total (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 10 tissues, sQTL in 2 (q < 0.05)
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.94 (unconstrained)
• MANE Select transcript: NM_002692
• Notable: 477 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9178
Approved symbol	POLE2
Name	DNA polymerase epsilon 2, accessory subunit
Location	14q21.3
Locus type	gene with protein product
Status	Approved
Aliases	DPE2
Ensembl gene	ENSG00000100479
Ensembl biotype	protein_coding
OMIM	602670
Entrez	5427

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000216367

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 3: 4, TSL 5: 1

ENST00000216367, ENST00000539565, ENST00000553805, ENST00000553850, ENST00000554377, ENST00000554396, ENST00000554671, ENST00000554851, ENST00000555724, ENST00000556937, ENST00000700174, ENST00000700175, ENST00000700176, ENST00000960548, ENST00000960549, ENST00001073301, ENST00001132877

RefSeq mRNA: 5 — MANE Select: NM_002692 NM_001197330, NM_001197331, NM_001348384, NM_001348385, NM_002692

CCDS: CCDS32073, CCDS55914, CCDS55915

Canonical transcript exons

ENST00000216367 — 19 exons

Exon	Start	End
ENSE00000940761	49674350	49674427
ENSE00001507517	49664626	49664674
ENSE00001507518	49665107	49665163
ENSE00002521948	49688136	49688214
ENSE00003484987	49674123	49674216
ENSE00003497125	49666330	49666413
ENSE00003533273	49653990	49654067
ENSE00003608845	49679725	49679800
ENSE00003618568	49655671	49655843
ENSE00003642639	49655005	49655094
ENSE00003646275	49663315	49663387
ENSE00003668663	49669524	49669598
ENSE00003695222	49683593	49683693
ENSE00003979029	49647293	49647360
ENSE00003979034	49643555	49643670
ENSE00003979035	49654155	49654214
ENSE00003979038	49654784	49654838
ENSE00003979039	49650265	49650441
ENSE00003979042	49651269	49651377

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 94.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5339 / max 178.9283, expressed in 1345 samples.

Highest expression (Bgee): primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, secondary oocyte, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLE2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Colon Sigmoid	eqtl	8.8e-04	+0.21	14:49569170:T:TAA
Liver	eqtl	4.5e-03	-0.36	14:49637458:A:G
Thyroid	eqtl	6.0e-03	+0.18	14:49546606:G:C
Skin Sun Exposed Lower leg	sqtl	9.5e-03	+0.32	14:49654140:C:T
Colon Transverse	eqtl	1.7e-02	+0.25	14:49845210:A:T
Whole Blood	eqtl	1.8e-02	+0.40	14:49753270:A:AC
Skin Not Sun Exposed Suprapubic	eqtl	2.9e-02	-0.13	14:49610746:TAG:T
Adipose Subcutaneous	sqtl	3.2e-02	-0.48	14:49928401:C:T
Testis	eqtl	3.3e-02	-0.46	14:50055980:G:C
Cells Cultured fibroblasts	eqtl	3.5e-02	+0.05	14:50400754:A:G
Artery Aorta	eqtl	3.7e-02	-0.58	14:49974061:C:T
Esophagus Mucosa	eqtl	4.6e-02	+0.24	14:50415196:A:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
143089	6.8978	1302
143090	0.6362	397

Top tissues by expression

showing 100 of 290 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.94	gold quality
ventricular zone	UBERON:0003053	85.02	gold quality
secondary oocyte	CL:0000655	84.94	gold quality
mucosa of transverse colon	UBERON:0004991	83.36	gold quality
adrenal tissue	UBERON:0018303	82.90	gold quality
rectum	UBERON:0001052	82.27	gold quality
ganglionic eminence	UBERON:0004023	82.00	gold quality
right uterine tube	UBERON:0001302	81.28	gold quality
esophagus mucosa	UBERON:0002469	80.97	gold quality
ectocervix	UBERON:0012249	80.92	gold quality
right ovary	UBERON:0002118	80.50	gold quality
embryo	UBERON:0000922	80.19	gold quality
right lobe of liver	UBERON:0001114	79.37	gold quality
cervix squamous epithelium	UBERON:0006922	79.28	gold quality
bone marrow	UBERON:0002371	79.18	gold quality
left ovary	UBERON:0002119	79.04	gold quality
endocervix	UBERON:0000458	78.80	gold quality
right lobe of thyroid gland	UBERON:0001119	78.74	gold quality
body of uterus	UBERON:0009853	78.64	gold quality
metanephros cortex	UBERON:0010533	78.45	gold quality
oocyte	CL:0000023	78.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.40	gold quality
body of pancreas	UBERON:0001150	77.91	gold quality
vagina	UBERON:0000996	77.61	gold quality
transverse colon	UBERON:0001157	77.48	gold quality
lower esophagus mucosa	UBERON:0035834	77.44	gold quality
left lobe of thyroid gland	UBERON:0001120	77.17	gold quality
ovary	UBERON:0000992	77.04	gold quality
bone element	UBERON:0001474	76.94	gold quality
esophagus	UBERON:0001043	76.64	gold quality
stromal cell of endometrium	CL:0002255	76.45	gold quality
calcaneal tendon	UBERON:0003701	76.40	gold quality
spleen	UBERON:0002106	76.36	gold quality
skin of abdomen	UBERON:0001416	76.06	gold quality
thyroid gland	UBERON:0002046	76.04	gold quality
body of stomach	UBERON:0001161	75.87	gold quality
skin of leg	UBERON:0001511	75.81	gold quality
adenohypophysis	UBERON:0002196	75.66	gold quality
vermiform appendix	UBERON:0001154	75.62	gold quality
minor salivary gland	UBERON:0001830	75.50	gold quality
bone marrow cell	CL:0002092	75.25	gold quality
testis	UBERON:0000473	74.97	gold quality
right testis	UBERON:0004534	74.96	gold quality
small intestine	UBERON:0002108	74.95	gold quality
left testis	UBERON:0004533	74.87	gold quality
left uterine tube	UBERON:0001303	74.68	gold quality
tibial nerve	UBERON:0001323	74.49	gold quality
cerebellar hemisphere	UBERON:0002245	74.33	gold quality
descending thoracic aorta	UBERON:0002345	74.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	74.04	gold quality
cerebellar cortex	UBERON:0002129	73.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.90	gold quality
intestine	UBERON:0000160	73.71	gold quality
stomach	UBERON:0000945	73.57	gold quality
ascending aorta	UBERON:0001496	73.54	gold quality
thoracic aorta	UBERON:0001515	73.47	gold quality
apex of heart	UBERON:0002098	73.44	gold quality
lymph node	UBERON:0000029	73.42	gold quality
left coronary artery	UBERON:0001626	73.34	gold quality
tongue squamous epithelium	UBERON:0006919	73.32	gold quality
colon	UBERON:0001155	73.27	gold quality
right lung	UBERON:0002167	73.24	gold quality
mouth mucosa	UBERON:0003729	73.07	gold quality
zone of skin	UBERON:0000014	73.02	gold quality
trabecular bone tissue	UBERON:0002483	73.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.00	gold quality
left adrenal gland cortex	UBERON:0035825	72.95	gold quality
large intestine	UBERON:0000059	72.94	gold quality
upper lobe of left lung	UBERON:0008952	72.94	gold quality
granulocyte	CL:0000094	72.80	gold quality
left adrenal gland	UBERON:0001234	72.73	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	72.72	gold quality
aorta	UBERON:0000947	72.57	gold quality
pancreas	UBERON:0001264	72.46	gold quality
pituitary gland	UBERON:0000007	72.36	gold quality
tibial artery	UBERON:0007610	72.24	gold quality
popliteal artery	UBERON:0002250	72.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.22	gold quality
lower esophagus	UBERON:0013473	72.21	gold quality
female reproductive system	UBERON:0000474	71.90	gold quality
prostate gland	UBERON:0002367	71.85	gold quality
right adrenal gland	UBERON:0001233	71.62	gold quality
sigmoid colon	UBERON:0001159	71.54	gold quality
uterine cervix	UBERON:0000002	71.49	gold quality
adrenal gland	UBERON:0002369	71.35	gold quality
coronary artery	UBERON:0001621	71.33	gold quality
upper lobe of lung	UBERON:0008948	71.27	gold quality
endometrium	UBERON:0001295	71.12	gold quality
right adrenal gland cortex	UBERON:0035827	71.05	gold quality
squamous epithelium	UBERON:0006914	70.93	silver quality
right atrium auricular region	UBERON:0006631	70.84	gold quality
cerebellum	UBERON:0002037	70.82	gold quality
omental fat pad	UBERON:0010414	70.59	gold quality
right coronary artery	UBERON:0001625	70.55	gold quality
smooth muscle tissue	UBERON:0001135	70.52	gold quality
peritoneum	UBERON:0002358	70.51	gold quality
saliva-secreting gland	UBERON:0001044	70.41	gold quality
uterus	UBERON:0000995	70.40	gold quality
ileal mucosa	UBERON:0000331	70.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.99
E-GEOD-75367	no	128.63
E-MTAB-4850	no	32.47

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	17.3	low
Cerebellum	tissue	6.9	not detected
Tonsil	tissue	5.8	medium
Thymus	tissue	5.3
Lymph node	tissue	4.9	low
Appendix	tissue	4.8	low
Rectum	tissue	4.5	not detected
Basal ganglia	tissue	4.1	not detected
Testis	tissue	4.0	low
Putamen	tissue	3.9
Ventral forebrain	tissue	3.9
Colon	tissue	3.6	not detected
Nucleus accumbens	tissue	3.5
Small intestine	tissue	3.5	not detected
Skin 1	tissue	3.4	medium
Retina	tissue	3.4
Olfactory bulb	tissue	3.3
Septum	tissue	3.3
Cerebral cortex	tissue	3.2	not detected
Occipital cortex	tissue	3.2
Liver	tissue	3.1	not detected
Amygdala	tissue	3.0
Placenta	tissue	2.9	medium
Corpus callosum	tissue	2.9
Hippocampal formation	tissue	2.9
Temporal cortex	tissue	2.9
Breast	tissue	2.8	low
Esophagus	tissue	2.8	medium
Entorhinal cortex	tissue	2.8
Prefrontal cortex	tissue	2.7
Hypothalamus	tissue	2.7
Retrosplenial and cingulate cortex	tissue	2.7
Retrosplenial cortex	tissue	2.7
Hippocampus	tissue	2.6	not detected
Postcentral gyrus	tissue	2.6
Insular cortex	tissue	2.6
Endometrium 1	tissue	2.5	not detected
Motor cortex	tissue	2.4
Duodenum	tissue	2.3	not detected
Somatosensory cortex	tissue	2.3
Midbrain	tissue	2.2
Locus coeruleus	tissue	2.2
Spinal cord	tissue	2.2
Stomach 1	tissue	2.1	not detected
Smooth muscle	tissue	2.1	not detected
Periaqueductal gray	tissue	2.0
Vagina	tissue	1.9	low
Superior colliculi	tissue	1.9
Substantia nigra	tissue	1.9
Ovary	tissue	1.8	low
Medulla oblongata	tissue	1.8
Pons	tissue	1.7
Thalamus	tissue	1.4
Prostate	tissue	1.4	not detected
Cervix	tissue	1.3	medium
Urinary bladder	tissue	1.3	low
Adipose tissue	tissue	1.1	not detected
Pancreas	tissue	1.1	not detected
Choroid plexus	tissue	1.1
Lung	tissue	1.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Parahippocampal cortex (white matter) (3.7), Vermis (3.7), Area parastriata, temporal (3.6), Parieto-temporal junction (white matter) (3.6), Periaquaductal grey, lateral (3.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F4, NFIC, SP1

miRNA regulators (miRDB)

Targeting POLE2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

13 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-3074-3P	97.83	67.26	922
HSA-MIR-4662A-3P	97.02	67.77	941

Functional genomics

gnomAD constraint: pLI 0.00134, LOEUF 1.94, missense Z -1.67 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000216367 — one region, missense o/e 0.94. DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KLE (-3.082), TUHR14TKB (-3.041), LN382 (-3.036), DK-MG (-2.758), SK-MM-2 (-2.681), SK-HEP-1 (-2.651), Daoy (-2.634), DEL (-2.61), HUP-T3 (-2.574), OUMS-23 (-2.573), EC-GI-10 (-2.564), VCaP (-2.56), HPAF-II (-2.544), U-118 MG (-2.477), MFE-280 (-2.471).

Literature-anchored findings (GeneRIF, showing 10)

• The solution structure of the N-terminal domain of human DNA polymerase epsilon subunit B revealed a domain that consists of a left-handed superhelical bundle. (PMID:18676977)
• found that mutations occurred in POLE2 in 5 out of 16 cases of human colon cancer examined. (PMID:20065316)
• Inhibition of DNA polymerases a, delra and e by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells,as novel strategy for gene therapy (PMID:25924900)
• Genetic Risk of Trigger Finger: Results of a Genomewide Association Study. (PMID:32740585)
• POLE2 facilitates the malignant phenotypes of glioblastoma through promoting AURKA-mediated stabilization of FOXM1. (PMID:35039475)
• POLE2 knockdown suppresses lymphoma progression via downregulating Wnt/beta-catenin signaling pathway. (PMID:37097331)
• Knockdown of HDAC10 inhibits POLE2-mediated DNA damage repair in NSCLC cells by increasing SP1 acetylation levels. (PMID:37657752)
• Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway. (PMID:38070189)
• POLE2 Regulates Apoptosis of Oral Squamous Cell Carcinoma Cells through the PI3K/AKT Signaling Pathway. (PMID:38079056)
• The Prognostic Hub Gene POLE2 Promotes BLCA Cell Growth via the PI3K/AKT Signaling Pathway. (PMID:38963027)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pole2	ENSDARG00000100028
mus_musculus	Pole2	ENSMUSG00000020974
rattus_norvegicus	Pole2	ENSRNOG00000004242
drosophila_melanogaster	PolE2	FBGN0035644
caenorhabditis_elegans		WBGENE00017237

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1197514) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 19 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal heart morphology	1
abnormal liver morphology	1
abnormal spleen morphology	1
enlarged spleen	1
enlarged lymph nodes	1
abnormal uterus morphology	1
small testis	1
microphthalmia	1
abnormal embryo turning	1
abnormal skin morphology	1
abnormal eye morphology	1
abnormal neural tube morphology	1
small heart	1
abnormal neural tube closure	1
abnormal midbrain development	1
impaired glucose tolerance	1
increased prepulse inhibition	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Cryptococcus deneoformans JEC21	P0CN24	100.0%	Diamond
Cryptococcus deneoformans B-3501A	P0CN25	100.0%	Diamond
Bos taurus	A7YWS7	94.9%	Diamond
Gallus gallus	Q5ZKQ6	82.9%	Diamond
Arabidopsis thaliana	Q500V9	37.5%	Diamond
Dictyostelium discoideum	Q54Y85	36.4%	Diamond
Schizosaccharomyces pombe 972h-	O94263	35.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KLHDC1	protein-coding	122773
KLHDC2	protein-coding	23588
DNAAF2	protein-coding	55172
NEMF	protein-coding	9147
MGAT2	protein-coding	4247
LRR1	protein-coding	122769
RPL36AL	protein-coding	6166
RN7SL3	scRNA	378707
RN7SL2	scRNA	378706

Protein

Protein identifiers

DNA polymerase epsilon subunit 2 — P56282 (reviewed: P56282)

Alternative names: DNA polymerase II subunit 2, DNA polymerase epsilon subunit B

All UniProt accessions (6): A0A8V8TPE4, A0A8V8TPU0, A0A8V8TQQ0, A0A8V8TR10, P56282, U3KQ22

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.

Subcellular location. Nucleus.

Miscellaneous. In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.

Similarity. Belongs to the DNA polymerase epsilon subunit B family.

Isoforms (3)

UniProt ID	Names	Canonical?
P56282-1	1	yes
P56282-2	2
P56282-3	3

RefSeq proteins (5): NP_001184259, NP_001184260, NP_001335313, NP_001335314, NP_002683* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007185	DNA_pol_a/d/e_bsu	Domain
IPR016266	POLE2	Family
IPR024639	DNA_pol_e_bsu_N	Domain

Pfam: PF04042, PF12213

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 (67 total): helix 25, strand 25, turn 9, sequence variant 3, splice variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
5VBN	Crystal Structure of human DNA polymerase epsilon B-subunit in complex with C-terminal …	X-RAY DIFFRACTION	2.35
7PLO	H. sapiens replisome-CUL2/LRR1 complex	ELECTRON MICROSCOPY	2.8
7PFO	Core human replisome	ELECTRON MICROSCOPY	3.2
2V6Z	Solution Structure of Amino-Terminal Domain of Human DNA Polymerase Epsilon Subunit B	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56282-F1	93.16	0.81

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm; vesicles

Antibody reliability (HPA): IH uncertain · IF supported

Function

Pathways and Gene Ontology

Reactome pathways

10 curated (TAS) of 30; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

30 pathways:

ID	Pathway	Evidence
R-HSA-68962	Activation of the pre-replicative complex	curated
R-HSA-68952	DNA replication initiation	curated
R-HSA-5696400	Dual Incision in GG-NER	curated
R-HSA-6782135	Dual incision in TC-NER	curated
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER	curated
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER	curated
R-HSA-5685942	HDR through Homologous Recombination (HRR)	curated
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair	curated
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex	curated
R-HSA-5656169	Termination of translesion DNA synthesis	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-73893	DNA Damage Bypass	—
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-69306	DNA Replication	—
R-HSA-69002	DNA Replication Pre-Initiation	—
R-HSA-69206	G1/S Transition	—
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)	—
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	—
R-HSA-5693538	Homology Directed Repair	—
R-HSA-453279	Mitotic G1 phase and G1/S transition	—
R-HSA-5696398	Nucleotide Excision Repair	—
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway	—
R-HSA-73933	Resolution of Abasic Sites (AP sites)	—
R-HSA-69242	S Phase	—
R-HSA-69239	Synthesis of DNA	—
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)	—
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	—

MSigDB gene sets: 298 (showing top): E2F_Q4, REACTOME_DNA_REPLICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, E2F_Q4_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, E2F4DP1_01, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GENTILE_RESPONSE_CLUSTER_D3, GOBP_DNA_DAMAGE_TOLERANCE, KAUFFMANN_DNA_REPAIR_GENES, PUJANA_CHEK2_PCC_NETWORK, WEI_MYCN_TARGETS_WITH_E_BOX

GO Biological Process (5): DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261), DNA repair (GO:0006281), error-prone translesion synthesis (GO:0042276), DNA metabolic process (GO:0006259)

GO Molecular Function (3): DNA binding (GO:0003677), DNA-directed DNA polymerase activity (GO:0003887), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), epsilon DNA polymerase complex (GO:0008622), nuclear body (GO:0016604), nucleus (GO:0005634), chromosome (GO:0005694), nuclear lumen (GO:0031981)

Reactome top-level categories

15 top-level categories:

Category	Pathways
DNA Damage Bypass	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
DNA Repair	2
Nucleotide Excision Repair	2
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
Resolution of Abasic Sites (AP sites)	1
Cell Cycle, Mitotic	1
DNA Double-Strand Break Repair	1
Homology Directed Repair	1

GO top-level categories

19 GO namespaces:

Category	Terms
DNA metabolic process	2
intracellular membraneless organelle	2
DNA biosynthetic process	1
DNA replication	1
DNA damage response	1
translesion synthesis	1
nucleic acid metabolic process	1
nucleic acid binding	1
DNA polymerase activity	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
nuclear chromosome	1
DNA polymerase complex	1
nuclear protein-containing complex	1
nucleoplasm	1
intracellular membrane-bounded organelle	1
nucleus	1
intracellular organelle lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
DNA-templated DNA replication	BP	direct assay
epsilon DNA polymerase complex	CC	direct assay
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,209 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLE2	POLE	Q07864	960
POLE2	POLE4	Q9NR33	951
POLE2	POLE3	Q9NRF9	945
POLE2	POLA2	Q14181	739
POLE2	POLD2	P49005	718
POLE2	POLA1	P09884	711
POLE2	RFC4	P35249	703
POLE2	POLD1	P28340	698
POLE2	MCM4	P33991	658
POLE2	MCM6	Q14566	657
POLE2	GINS1	Q14691	651
POLE2	CDC45	O75419	644
POLE2	CHRAC1	Q9NRG0	639
POLE2	RFC3	P40938	627
POLE2	GINS2	Q9Y248	625

IntAct

Human interaction partners of POLE2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

19 partners by confidence:

Partner	Interaction type	MIscore	Records
POLE	physical association	0.860	10
TRIM27	physical association	0.780	7
MAPRE1	physical association	0.720	6
POLE3	association	0.690	1
POLE4	association	0.640	1
EXOSC4	physical association	0.560	5
AGFG1	physical association	0.560	3
HEL-S-30	physical association	0.560	3
REL	physical association	0.560	3
SORBS3	physical association	0.560	3
TBX15	physical association	0.560	3
UBQLN2	physical association	0.560	3
ZBED1	physical association	0.560	3
ZNF620	physical association	0.560	3
CYP4F12	association	0.560	2
EEF1A1	physical association	0.000	1
ERG28	physical association	0.000	1
KAT5	physical association	0.000	1
TLE1	physical association	0.000	1

BioGRID (109 interactions; top human partners by supporting records): POLE (Affinity Capture-MS; 11 records), POLE3 (Affinity Capture-MS; 6 records), POLE4 (Affinity Capture-MS; 4 records), DNAJC7 (Affinity Capture-MS; 3 records), KLK5 (Affinity Capture-MS; 3 records), LRRC46 (Affinity Capture-MS; 3 records), ARL4C (Affinity Capture-MS; 2 records), C16orf45 (Affinity Capture-MS; 2 records), C6orf141 (Affinity Capture-MS; 2 records), CD79B (Affinity Capture-MS; 2 records), CYP4F12 (Affinity Capture-MS; 2 records), FAM46A (Affinity Capture-MS; 2 records), KLK11 (Affinity Capture-MS; 2 records), KRAS (Synthetic Lethality; 2 records), MAPRE1 (Two-hybrid; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
POLE2	“form complex”	“DNA polymerase epsilon”	binding

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
★ RC complex, S-phase-specific	23	POLD4, POLE2, POLE4, CCNA2, CDK2, POLD2, POLD3, RFC2, POLE, RFC1, RFC5, RPA3, LIG1, PARP1, POLA1, POLD1, RFC3, RPA2, POLA2, POLE3, RFC4, RPA1, TOP1
★ DNA synthesome complex, breast cancer MCF7 cells	23	POLA2, POLD3, POLE4, PRIM1, RFC1, RPA1, PCNA, POLD4, POLE2, POLE3, RFC4, TOP1, POLA1, RFC2, RFC3, RFC5, RPA2, RPA3, TOP2A, POLD1, POLD2, POLE, PRIM2
★ DNA synthesome complex, breast cancer cells	20	POLD3, POLE4, RFC2, RFC3, POLA2, POLE3, LIG1, PARP1, PCNA, POLD2, PRIM1, PRIM2, RFC1, RFC4, POLD4, POLE, POLE2, RFC5, POLA1, POLD1
★ RC complex, G2/M-phase-specific	19	CCNB1, POLA1, POLA2, POLD2, RPA1, RPA2, CDK1, POLD3, RFC1, RFC2, RPA3, POLD1, POLD4, POLE, POLE3, PARP1, POLE2, POLE4, TOP1
★ DNA polymerase epsilon	4	POLE, POLE2, POLE3, POLE4

Disease & clinical

Genetic variants

Variant evidence for POLE2: 477 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	272
Likely benign	156
Benign	13

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 1,622):

Position(s)	Effect	Δscore	Sites
14:49651267–49651268	donor_loss	1.0000	3
14:49651378–49651379	acceptor_loss	1.0000	6
14:49655003–49655004	donor_loss	1.0000	4
14:49655095–49655096	acceptor_loss	1.0000	3
14:49674121–49674122	donor_loss	1.0000	5
14:49679752	donor_gain	1.0000
14:49683591–49683592	donor_loss	1.0000	5
14:49683694–49683695	acceptor_loss	1.0000	6
14:49651268	donor_loss	0.9900
14:49653988–49653989	donor_loss	0.9900	5

AlphaMissense

1,154 missense substitutions predicted likely pathogenic (of 3,471 scored), across 316 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D199	8	0.979	0.993
F147	8	0.978	0.996
D482	8	0.970	0.996
D369	8	0.961	0.987
F509	8	0.940	0.996
F502	8	0.934	0.990
F325	8	0.923	0.993
F14	8	0.880	0.965
F361	8	0.874	0.992
F235	8	0.870	0.996
D466	8	0.863	0.969
F398	8	0.811	0.944
D292	8	0.807	0.958
E246	7	0.959	0.976
N401	7	0.955	0.998
F487	7	0.948	0.989
R143	7	0.930	0.988
E198	7	0.919	0.968
D296	7	0.918	0.953
F163	7	0.916	0.986

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	7.54e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.00017
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000221
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000263
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000467
Kidney Chromophobe (TCGA)	unfavorable	0.000504

Disease associations

OMIM: gene MIM:602670 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
combined immunodeficiency	Limited	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
combined immunodeficiency due to POLE2 deficiency	Limited	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	green

Mondo (1): combined immunodeficiency (MONDO:0015131)

GWAS associations

1 associations:

Study	Trait	p-value
GCST011318_2	Trigger finger	1e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0010822	stenosing tenosynovitis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363042 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	4
(+)-JQ1 compound	decreases expression	3
Tretinoin	decreases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Estradiol	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cadmium Chloride	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
dicrotophos	decreases expression	1
lasiocarpine	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
phenethyl isothiocyanate	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 80 trials:

NCT	Phase	Status	Title
NCT02737384	Phase 2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
NCT02871778	Phase 2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	Phase 2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT05737485	Phase 1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	Phase 1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	Phase 1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion
NCT04902807	Not specified	COMPLETED	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency
NCT04901715	Early Phase 1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide
NCT00783887	Not specified	COMPLETED	Diagnosis of Primary Ciliary Dyskinesia
NCT00807482	Not specified	RECRUITING	Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
NCT01070914	Not specified	UNKNOWN	Early Detection and Characterization of Primary Ciliary Dyskinesia
NCT01155115	Not specified	COMPLETED	Inflammatory and Microbiologic Markers in Sputum: Comparing Cystic Fibrosis With Primary Ciliary Dyskinesia
NCT01246258	Not specified	COMPLETED	Otolith Function in Patients With Primary Ciliary Dyskinesia
NCT01929356	Not specified	UNKNOWN	Chest Physiotherapy and Lung Function in Primary Ciliary Dyskinesia
NCT02389049	Not specified	COMPLETED	Genetics of Primary Ciliary Dyskinesia
NCT02419365	Not specified	RECRUITING	International Primary Ciliary Dyskinesia (PCD) Registry
NCT02622061	Not specified	COMPLETED	NIOX VERO Nasal Application in Primary Ciliary Dyskinesia
NCT02699177	Not specified	UNKNOWN	In Vivo Measurements of Nasal Ciliary Beat Frequency by Using Interferometry
NCT02704455	Not specified	NOT_YET_RECRUITING	Registry Study on Primary Ciliary Dyskinesia in Chinese Children
NCT03271840	Not specified	COMPLETED	Registry for Primary Ciliary Dyskinesia
NCT03279965	Not specified	UNKNOWN	MRI in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03320382	Not specified	UNKNOWN	Multiple Breath Washout, a Clinimetric Dataset
NCT03370029	Not specified	COMPLETED	Respiratory Muscle Strength, Exercise Capacity and Physical Activity Levels in Children Primary Ciliary Dyskinesia
NCT03494894	Not specified	COMPLETED	Bacteriological Link Between Upper and Lower Airways in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03517865	Not specified	ACTIVE_NOT_RECRUITING	International Primary Ciliary Dyskinesia Cohort
NCT03606200	Not specified	RECRUITING	Swiss Primary Ciliary Dyskinesia Registry
NCT03704207	Not specified	RECRUITING	Utility of PCD Diagnostics to Improve Clinical Care
NCT03704896	Not specified	UNKNOWN	PRospective Observational Multicentre Study on VAriability of Lung Function in Stable PCD Patients
NCT03801395	Not specified	COMPLETED	PCD New Gene Discovery
NCT03809091	Not specified	UNKNOWN	WGS of Korean Idiopathic Bronchiectasis
NCT03832491	Not specified	COMPLETED	Effect of Game Based Approach on Oxygenation, Functional Capacity and Quality of Life in Primary Ciliary Dyskinesia
NCT04161313	Not specified	COMPLETED	Respiratory Function, Exercise Capacity and Peripheral Muscle Strength Among Patients With CF, PCD and Healthy Children
NCT04476433	Not specified	COMPLETED	Intervention in Chronic Pediatric Patients and Their Families.
NCT04489472	Not specified	UNKNOWN	The Effect of a Dietary Supplement Rich in Nitric Oxide in Patients Diagnosed With Primary Ciliary Dyskinesia.
NCT04602481	Not specified	RECRUITING	Living With Primary Ciliary Dyskinesia (Living With PCD)
NCT04611516	Not specified	RECRUITING	The Ear-Nose-Throat (ENT) Prospective International Cohort of PCD Patients (EPIC-PCD)
NCT04702243	Not specified	COMPLETED	Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults
NCT04717115	Not specified	UNKNOWN	Genotype/Phenotype Correlation With Focus on Lung Function in Primary Ciliary Dyskinesia (PCD)
NCT04793724	Not specified	COMPLETED	Respiratory Physiotherapy Performed by Simeox In Patients With Primary Ciliary Dyskinesia
NCT04858191	Not specified	COMPLETED	Utilizing Hyperpolarized 129Xe Magnetic Resonance Imaging in Children With Primary Ciliary Dyskinesia
NCT04895150	Not specified	COMPLETED	Upper Extremity Exercise Capacity, Muscle Oxygenation, Balance in Patients With Primary Ciliary Dyskinesia
NCT04919018	Not specified	COMPLETED	Characterizing the Upper Airway Manifestations in Primary Ciliary Dyskinesia and Primary Immunodeficiencies
NCT04949308	Not specified	UNKNOWN	Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia
NCT05040607	Not specified	COMPLETED	Physical Fitness, Exercise Capacity and Activities of Daily Living in Primary Ciliary Dyskinesia: a Retrospective Study
NCT05161858	Not specified	COMPLETED	Longitudinal Characterization of Respiratory Tract Exacerbations and Treatment Responses in Primary Ciliary Dyskinesia
NCT05287022	Not specified	RECRUITING	Use of Nasal Nitric Oxide Testing in Improving Primary Ciliary Dyskinesia Clinical Care
NCT05374720	Not specified	TERMINATED	Analysis of the Molecular Composition of Tubal Cilia in Patients With or Without Ectopic Pregnancy
NCT05685186	Not specified	COMPLETED	A Longitudinal, Observational Study of Primary Ciliary Dyskinesia in Adults
NCT05712798	Not specified	COMPLETED	Physiological Responses to Exercise Tests in Primary Ciliary Dyskinesia Compared With Healthy Individuals
NCT05816876	Not specified	COMPLETED	Muscle Function, Exercise Capacity and Physical Activity Level in Primary Ciliary Dyskinesia and Kartagener Syndrome