POLE (DNA polymerase epsilon, catalytic subunit)

2018-05-01   Enric Domingo 

\\\/ e-Mail Department of Oncology, University of Oxford, Oxford, United Kingdom \\\/ enric.domingo@oncology.ox.ac.uk





POLE gene is 63.6 kb long and composed of 49 coding exons, where the first and last one also have a UTR region.


The length of the transcript is 7840 bp and results in a protein of 2286 residues.



The POLE gene encodes for one of the four subunits that form Polε (DNA polymerase epsilon) together with POLE2, POLE3 and POLE4 genes. This protein is one of the main DNA replicases in eukaryotes and is responsible of the replication of the leading strand. POLE contains both the catalytic active site and the proofreading exonuclease domain (residues 223-517). Accordingly, the POLE gene confers to Polε both replicative and 3 to 5 repair capabilities for the new strand.


Broadly expressed.




Polε is responsible of the polymerization of the leading strand during DNA replication in yeast and humans. It also possesses 3 to 5 exonuclease capability to repair missincorporated nucleotides during DNA replication. Polε is also involved in DNA repair pathways such as mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) or double-strand break repair.



A few missense germline mutations in the proofreading domain of POLE have been shown to be pathogenic such as W347C, N363K, D368V, L424V, P436S or Y458F. These are quite rare in the population although for unclear reasons they are more common than similar germline mutations in the polymerase gene POLD1. These mutations affect the exonuclease repair of Polε hence resulting in a mutation rate increase of about 100-fold. Accordingly, these tumours are usually called ultramutated.


Pathogenic somatic mutations in the proofreading domain of POLE have been found in some tumour types at moderate or rare frequencies. Some mutations in the polymerase domain have been suggested to be drivers but further research is required to validate these results.

Implicated in

Entity name
Different human sporadic cancers
Somatic pathogenic mutations in the proofreading domain of POLE have been found in 8% of endometrial tumours and at lower frequencies in other tumour types such as colorectal, glioblastoma, ovary, prostate, breast or gastric cancer. These mutations seem to confer similar phenotypes regardless of the tumour tissue type. These are missense, heterozygous mutations where no second hit by either mutation or LOH seem to be required, and they are very early events, possibly initiating. Some mutations are hotspots such as P286R, S297F, V411L or S459F but other rarer mutations have also been identified (eg P286H/L, S297Y, F367S, L424V/I, P436R, M444K, A456P). These mutations affect the proofreading of the protein resulting in ultramutation with an overrepresentation of C>A. More specifically, POLE tumours have mutational signature 10 as reported by Alexandrov et al, with extremely prominent TCG>TTG and TCT>TAT substitutions and transcriptional strand bias. As a result, there is an overrepresentation of some specific missense mutations and nonsense mutations. In addition, it may explain why some cancer driver genes in POLE tumours tend to show mutations otherwise relatively uncommon such as R213X in TP53 or R88Q in PIK3CA. POLE tumours are hardly ever concomitant with microsatellite instability, although a few tumours with both phenotypes have been described, and do not seem to show chromosomal instability as their karyotype is nearly diploid.
Patients with somatic POLE driver mutations are younger on average, although they have a broad range of ages. For colorectal cancer, most mutations are right-sided so they are relatively rare in rectal cancer.
POLE tumours in endometrial cancer, colorectal cancer and glioblastoma show excellent prognosis in early disease. Similar patterns are expected in any other tumour type although it is not formally proven due to the low frequency of these mutations. Such good prognosis is because of very high immunogenicity with upregulation of immune checkpoint and other immunosuppressive genes. Accordingly, POLE proofreading pathogenic mutation is also a promising candidate biomarker for checkpoint blockade immunotherapy. They may also be sensitive to treatment with nucleoside analogs as they increase the mutation burden to a level where tumour cells are not viable.
Entity name
Proofreading-associated polyposis (PPAP)
Autosomal dominant disease with high risk for endometrial and/or colorectal adenoma or carcinoma due to germline mutations in POLE or POLD1 genes.
Probably good prognosis in early disease as found with POLE somatic mutations, although not formally proven. Similarly, these patients are likely to respond to checkpoint blockade immunotherapy.


Pubmed IDLast YearTitleAuthors
239455922013Signatures of mutational processes in human cancer.Alexandrov LB et al
261333942016POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Bellido F et al
290563442017Comprehensive Analysis of Hypermutation in Human Cancer.Campbell BB et al
235285592013DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.Church DN et al
255052302015Prognostic significance of POLE proofreading mutations in endometrial cancer.Church DN et al
284040932016Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study.Domingo E et al
283448702017Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.Eggink FA et al
257407842015Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis.Erson-Omay EZ et al
245833932014Replicative DNA polymerase mutations in cancer.Heitzer E et al
276835562016Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy.Johanns TM et al
232634902013Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Palles C et al
268225752016A panoply of errors: polymerase proofreading domain mutations in cancer.Rayner E et al
296040632018Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.Temko D et al
245012772014New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.Valle L et al
295595622018Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues.Van Gool IC et al
271413332016POLE proofreading mutation, immune response and prognosis in endometrial cancer.van Gool IC et al

Other Information

Locus ID:

NCBI: 5426
MIM: 174762
HGNC: 9177
Ensembl: ENSG00000177084


dbSNP: 5426
ClinVar: 5426
TCGA: ENSG00000177084


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Purine metabolismKEGGko00230
Pyrimidine metabolismKEGGko00240
DNA replicationKEGGko03030
Base excision repairKEGGko03410
Nucleotide excision repairKEGGko03420
Purine metabolismKEGGhsa00230
Pyrimidine metabolismKEGGhsa00240
DNA replicationKEGGhsa03030
Base excision repairKEGGhsa03410
Nucleotide excision repairKEGGhsa03420
Metabolic pathwaysKEGGhsa01100
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
DNA polymerase epsilon complexKEGGhsa_M00263
DNA polymerase epsilon complexKEGGM00263
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1/S TransitionREACTOMER-HSA-69206
Activation of the pre-replicative complexREACTOMER-HSA-68962
Synthesis of DNAREACTOMER-HSA-69239
DNA replication initiationREACTOMER-HSA-68952
M/G1 TransitionREACTOMER-HSA-68874
DNA Replication Pre-InitiationREACTOMER-HSA-69002
Chromosome MaintenanceREACTOMER-HSA-73886
Telomere MaintenanceREACTOMER-HSA-157579
Extension of TelomeresREACTOMER-HSA-180786
Telomere C-strand (Lagging Strand) SynthesisREACTOMER-HSA-174417
Telomere C-strand synthesis initiationREACTOMER-HSA-174430
DNA ReplicationREACTOMER-HSA-69306
Base Excision RepairREACTOMER-HSA-73884
Resolution of Abasic Sites (AP sites)REACTOMER-HSA-73933
Resolution of AP sites via the multiple-nucleotide patch replacement pathwayREACTOMER-HSA-110373
PCNA-Dependent Long Patch Base Excision RepairREACTOMER-HSA-5651801
DNA Damage BypassREACTOMER-HSA-73893
Recognition of DNA damage by PCNA-containing replication complexREACTOMER-HSA-110314
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA templateREACTOMER-HSA-110313
Termination of translesion DNA synthesisREACTOMER-HSA-5656169
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
Dual Incision in GG-NERREACTOMER-HSA-5696400
Gap-filling DNA repair synthesis and ligation in GG-NERREACTOMER-HSA-5696397
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Dual incision in TC-NERREACTOMER-HSA-6782135
Gap-filling DNA repair synthesis and ligation in TC-NERREACTOMER-HSA-6782210


Pubmed IDYearTitleCitations
232634902013Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.319
261810002015Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1.121
235285592013DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.105
224659572012DNA polymerase δ and ζ switch by sharing accessory subunits of DNA polymerase δ.85
234474012013Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers.85
252286592014Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.84
258783342015POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.70
276835562016Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy.70
224743842012Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis.66
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62


Enric Domingo

POLE (DNA polymerase epsilon, catalytic subunit)

Atlas Genet Cytogenet Oncol Haematol. 2018-05-01

Online version: http://atlasgeneticsoncology.org/gene/41773/pole-(dna-polymerase-epsilon-catalytic-subunit)