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POLE (DNA polymerase epsilon, catalytic subunit)

Written2018-05Enric Domingo
/ e-Mail Department of Oncology, University of Oxford, Oxford, United Kingdom /

Abstract Review on POLE, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords POLE; DNA repair; DNA replication; DNA replicase

(Note : for Links provided by Atlas : click)


HGNC Alias symbPOLE1
HGNC Alias nameDNA polymerase epsilon catalytic subunit A
HGNC Previous namepolymerase (DNA directed), epsilon
 polymerase (DNA) epsilon, catalytic subunit
LocusID (NCBI) 5426
Atlas_Id 41773
Location 12q24.33  [Link to chromosome band 12q24]
Location_base_pair Starts at 132623762 and ends at 132687342 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping POLE.png]
Local_order 132,623,762-132,687,359
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description POLE gene is 63.6 kb long and composed of 49 coding exons, where the first and last one also have a UTR region.
Transcription The length of the transcript is 7840 bp and results in a protein of 2286 residues.


Description 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.
Expression Broadly expressed.
Localisation Nuclear.
Function 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.


Germinal 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.
Somatic 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 Different human sporadic cancers
Note 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.
Disease 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.
Prognosis 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 Proofreading-associated polyposis (PPAP)
Disease Autosomal dominant disease with high risk for endometrial and/or colorectal adenoma or carcinoma due to germline mutations in POLE or POLD1 genes.
Prognosis 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.


Signatures of mutational processes in human cancer
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR
Nature 2013 Aug 22;500(7463):415-21
PMID 23945592
POLE 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, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, Pons T, González S, Iglesias S, Darder E, Piñol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lázaro C, Capellá G, Puente XS, Valle L
Genet Med 2016 Apr;18(4):325-32
PMID 26133394
Comprehensive Analysis of Hypermutation in Human Cancer
Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A
Cell 2017 Nov 16;171(5):1042-1056
PMID 29056344
DNA polymerase and δ exonuclease domain mutations in endometrial cancer
Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV; NSECG Collaborators, Kaur K, Taylor J, Tomlinson IP
Hum Mol Genet 2013 Jul 15;22(14):2820-8
PMID 23528559
Prognostic significance of POLE proofreading mutations in endometrial cancer
Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, Noske A, Amant F, Tomlinson IP, Wild PJ, Lambrechts D, Jürgenliemk-Schulz IM, Jobsen JJ, Smit VT, Creutzberg CL, Bosse T
J Natl Cancer Inst 2014 Dec 12;107(1):402
PMID 25505230
Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study
Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, Fessler E, Medema JP, Boot A, Morreau H, van Wezel T, Liefers GJ, Lothe RA, Danielsen SA, Sveen A, Nesbakken A, Zlobec I, Lugli A, Koelzer VH, Berger MD, Castellví-Bel S, Muñoz J; Epicolon consortium, de Bruyn M, Nijman HW, Novelli M, Lawson K, Oukrif D, Frangou E, Dutton P, Tejpar S, Delorenzi M, Kerr R, Kerr D, Tomlinson I, Church DN
Lancet Gastroenterol Hepatol 2016 Nov;1(3):207-216
PMID 28404093
Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition
Eggink FA, Van Gool IC, Leary A, Pollock PM, Crosbie EJ, Mileshkin L, Jordanova ES, Adam J, Freeman-Mills L, Church DN, Creutzberg CL, De Bruyn M, Nijman HW, Bosse T
Oncoimmunology 2016 Dec 9;6(2):e1264565
PMID 28344870
Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
Erson-Omay EZ, alayan AO, Schultz N, Weinhold N, Omay SB, Özduman K, Köksal Y, Li J, Serin Harmanci A, Clark V, Carrión-Grant G, Baranoski J, alar C, Barak T, Coskun S, Baran B, Köse D, Sun J, Bakirciolu M, Moliterno Günel J, Pamir MN, Mishra-Gorur K, Bilguvar K, Yasuno K, Vortmeyer A, Huttner AJ, Sander C, Günel M
Neuro Oncol 2015 Oct;17(10):1356-64
PMID 25740784
Replicative DNA polymerase mutations in cancer
Heitzer E, Tomlinson I
Curr Opin Genet Dev 2014 Feb;24:107-13
PMID 24583393
Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy
Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S, Ansstas G, Mardis ER, Dunn GP
Cancer Discov 2016 Nov;6(11):1230-1236
PMID 27683556
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas
Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I
Nat Genet 2013 Feb;45(2):136-44
PMID 23263490
A panoply of errors: polymerase proofreading domain mutations in cancer
Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN
Nat Rev Cancer 2016 Feb;16(2):71-81
PMID 26822575
Somatic 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, Van Gool IC, Rayner E, Glaire M, Makino S, Brown M, Chegwidden L, Palles C, Depreeuw J, Beggs A, Stathopoulou C, Mason J, Baker AM, Williams M, Cerundolo V, Rei M, Taylor JC, Schuh A, Ahmed A, Amant F, Lambrechts D, Smit VT, Bosse T, Graham TA, Church DN, Tomlinson I
J Pathol 2018 Mar 31
PMID 29604063
New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis
Valle L, Hernández-Illán E, Bellido F, Aiza G, Castillejo A, Castillejo MI, Navarro M, Seguí N, Vargas G, Guarinos C, Juarez M, Sanjuán X, Iglesias S, Alenda C, Egoavil C, Segura , Juan MJ, Rodriguez-Soler M, Brunet J, González S, Jover R, Lázaro C, Capellá G, Pineda M, Soto JL, Blanco I
Hum Mol Genet 2014 Jul 1;23(13):3506-12
PMID 24501277
Adjuvant Treatment for POLE Proofreading Domain-Mutant Cancers: Sensitivity to Radiotherapy, Chemotherapy, and Nucleoside Analogues
Van Gool IC, Rayner E, Osse EM, Nout RA, Creutzberg CL, Tomlinson IPM, Church DN, Smit VTHBM, de Wind N, Bosse T, Drost M
Clin Cancer Res 2018 Mar 20
PMID 29559562
POLE proofreading mutation, immune response and prognosis in endometrial cancer
van Gool IC, Bosse T, Church DN
Oncoimmunology 2015 Aug 12;5(3):e1072675
PMID 27141333


This paper should be referenced as such :
Enric Domingo
POLE (DNA polymerase epsilon, catalytic subunit)
Atlas Genet Cytogenet Oncol Haematol. 2019;23(3):53-55.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(12;12)(q24;q24) POLE::FBRSL1

External links


HGNC (Hugo)POLE   9177
LRG (Locus Reference Genomic)LRG_789
Atlas Explorer : (Salamanque)POLE
Entrez_Gene (NCBI)POLE    DNA polymerase epsilon, catalytic subunit
GeneCards (Weizmann)POLE
Ensembl hg19 (Hinxton)ENSG00000177084 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000177084 [Gene_View]  ENSG00000177084 [Sequence]  chr12:132623762-132687342 [Contig_View]  POLE [Vega]
ICGC DataPortalENSG00000177084
Genatlas (Paris)POLE
SOURCE (Princeton)POLE
Genetics Home Reference (NIH)POLE
Genomic and cartography
GoldenPath hg38 (UCSC)POLE  -     chr12:132623762-132687342 -  12q24.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)POLE  -     12q24.33   [Description]    (hg19-Feb_2009)
GoldenPathPOLE - 12q24.33 [CytoView hg19]  POLE - 12q24.33 [CytoView hg38]
Genome Data Viewer NCBIPOLE [Mapview hg19]  
OMIM174762   615083   615139   618336   
Gene and transcription
Genbank (Entrez)AF128542 AF128544 AK025087 AK093003 AK128248
RefSeq transcript (Entrez)NM_006231
Consensus coding sequences : CCDS (NCBI)POLE
Gene ExpressionPOLE [ NCBI-GEO ]   POLE [ EBI - ARRAY_EXPRESS ]   POLE [ SEEK ]   POLE [ MEM ]
Gene Expression Viewer (FireBrowse)POLE [ Firebrowse - Broad ]
GenevisibleExpression of POLE in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5426
GTEX Portal (Tissue expression)POLE
Human Protein AtlasENSG00000177084-POLE [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ07864   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ07864  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ07864
Domains : Interpro (EBI)DNA-dir_DNA_pol_B    DNA-dir_DNA_pol_B_exonuc    DNA-dir_DNA_pol_B_multi_dom    DNA/RNA_pol_sf    DNA_pol_B_C    DNA_pol_e_suA_C    POL2    RNaseH-like_sf    RNaseH_sf   
Domain families : Pfam (Sanger)DNA_pol_B (PF00136)    DNA_pol_B_exo1 (PF03104)    DUF1744 (PF08490)   
Domain families : Pfam (NCBI)pfam00136    pfam03104    pfam08490   
Domain families : Smart (EMBL)DUF1744 (SM01159)  POLBc (SM00486)  
Conserved Domain (NCBI)POLE
PDB Europe5VBN   
Structural Biology KnowledgeBase5VBN   
SCOP (Structural Classification of Proteins)5VBN   
CATH (Classification of proteins structures)5VBN   
AlphaFold pdb e-kbQ07864   
Human Protein Atlas [tissue]ENSG00000177084-POLE [tissue]
Protein Interaction databases
IntAct (EBI)Q07864
Complex Portal (EBI)Q07864 CPX-2108 epsilon DNA polymerase complex
Ontologies - Pathways
Ontology : AmiGOG1/S transition of mitotic cell cycle  nucleotide binding  mitotic cell cycle  DNA synthesis involved in DNA repair  DNA binding  DNA binding  chromatin binding  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  plasma membrane  DNA replication  DNA replication initiation  leading strand elongation  base-excision repair, gap-filling  base-excision repair, gap-filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  zinc ion binding  single-stranded DNA 3'-5' exodeoxyribonuclease activity  epsilon DNA polymerase complex  epsilon DNA polymerase complex  DNA replication proofreading  embryonic organ development  4 iron, 4 sulfur cluster binding  nucleic acid phosphodiester bond hydrolysis  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  nucleotide binding  mitotic cell cycle  DNA synthesis involved in DNA repair  DNA binding  DNA binding  chromatin binding  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  plasma membrane  DNA replication  DNA replication initiation  leading strand elongation  base-excision repair, gap-filling  base-excision repair, gap-filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  zinc ion binding  single-stranded DNA 3'-5' exodeoxyribonuclease activity  epsilon DNA polymerase complex  epsilon DNA polymerase complex  DNA replication proofreading  embryonic organ development  4 iron, 4 sulfur cluster binding  nucleic acid phosphodiester bond hydrolysis  
Pathways : KEGGPurine metabolism    Pyrimidine metabolism    DNA replication    Base excision repair    Nucleotide excision repair    HTLV-I infection   
REACTOMEQ07864 [protein]
REACTOME PathwaysR-HSA-68962 [pathway]   
NDEx NetworkPOLE
Atlas of Cancer Signalling NetworkPOLE
Wikipedia pathwaysPOLE
Orthology - Evolution
GeneTree (enSembl)ENSG00000177084
Phylogenetic Trees/Animal Genes : TreeFamPOLE
Homologs : HomoloGenePOLE
Homology/Alignments : Family Browser (UCSC)POLE
Gene fusions - Rearrangements
Fusion : MitelmanPOLE::ANKS1B [12q24.33/12q23.1]  
Fusion : QuiverPOLE
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPOLE [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)POLE
Exome Variant ServerPOLE
GNOMAD BrowserENSG00000177084
Varsome BrowserPOLE
ACMGPOLE variants
Genomic Variants (DGV)POLE [DGVbeta]
DECIPHERPOLE [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPOLE 
ICGC Data PortalPOLE 
TCGA Data PortalPOLE 
Broad Tumor PortalPOLE
OASIS PortalPOLE [ Somatic mutations - Copy number]
Cancer Gene: CensusPOLE 
Somatic Mutations in Cancer : COSMICPOLE  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPOLE
Mutations and Diseases : HGMDPOLE
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)POLE
DoCM (Curated mutations)POLE
CIViC (Clinical Interpretations of Variants in Cancer)POLE
NCG (London)POLE
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM174762    615083    615139    618336   
Orphanet22105    23548   
Genetic Testing Registry POLE
NextProtQ07864 [Medical]
Target ValidationPOLE
Huge Navigator POLE [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDPOLE
Pharm GKB GenePA277
Clinical trialPOLE
DataMed IndexPOLE
PubMed177 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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