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POLD1 (DNA polymerase delta 1, catalytic subunit)

Written2018-05Enric Domingo
/ e-Mail Department of Oncology, University of Oxford, Oxford, United Kingdom / enric.domingo@oncology.ox.ac.uk

Abstract Review on POLD1, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords POLD1; DNA repair; DNA replication; DNA replicase

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPOLD
polymerase (DNA directed), delta 1, catalytic subunit (125kD)
polymerase (DNA) delta 1, catalytic subunit
Alias_symbol (synonym)CDC2
Other alias
HGNC (Hugo) POLD1
LocusID (NCBI) 5424
Atlas_Id 41770
Location 19q13.33  [Link to chromosome band 19q13]
Location_base_pair Starts at 50384323 and ends at 50418018 bp from pter ( according to hg19-Feb_2009)  [Mapping POLD1.png]
Local_order 50,384,339-50,418,014
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description POLD1 gene is 33.7 kb long and composed of 1 non-coding exon followed by 25 coding exons and one last exon with both coding and 3' UTR regions.
Transcription The length of the transcript is 3444 bp and results in a protein of 1107 residues.
Pseudogene There is a pseudogene in chr 6q13 (LOC100422453).

Protein

Description The POLD1 gene encodes for p125 which is one of the four subunits that form Polδ (DNA polymerase delta) together with POLD2, POLD3 and POLD4 genes. This protein is one of the main DNA replicases in eukaryotes and is responsible of the replication of the lagging strand. POLD1 contains both the catalytic active site and the proofreading exonuclease domain (residues 245-571). Accordingly, the POLD1 gene confers to Polδ both replicative and 3' to 5' repair capabilities for the new strand.
Expression Broadly expressed.
Localisation Nuclear.
Function Polδ is responsible of the polymerization of the lagging strand during DNA replication in yeast and humans. It also possesses 3' to 5' exonuclease capability to repair missincorporated nucleotides during DNA replication. Polδ 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.

Mutations

Germinal A few missense germline mutations in the proofreading domain of POLD1 have been shown to be pathogenic such as D316G/H, P327L, R409W, L474P or S478N. These are extremely rare in the population and affect the exonuclease repair of Polδ hence resulting in a mutation rate increase of about 100-fold. Accordingly, these tumours are usually called ultramutated.
Somatic Although some somatic mutations in POLD1 have been reported for different tumour types, most of them are very likely to be passengers. They are usually found either in non-hypermutated tumours or in hypermutated tumours due to mismatch repair deficiency. So far no POLD1 somatic mutation has clearly been shown to be pathogenic.

Implicated in

  
Entity Proofreading-associated polyposis (PPAP)
Disease Autosomal dominant disease with high risk for endometrial carcinoma and/or colorectal adenoma or colorectal carcinoma due to germline mutations in POLE or POLD1 genes.
Prognosis Probably good prognosis in early disease. Although not formally proven in POLD1 tumours, hypermutated tumours due to analog mutations in the polymerase gene POLE that shows a similar phenotype are highly immunogenic resulting in better prognosis. In addition, these patients are likely to respond to immune checkpoint inhibition.
  

Bibliography

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
 
Replicative DNA polymerase mutations in cancer
Heitzer E, Tomlinson I
Curr Opin Genet Dev 2014 Feb;24:107-13
PMID 24583393
 
POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies
Nicolas E, Golemis EA, Arora S
Gene 2016 Sep 15;590(1):128-41
PMID 27320729
 
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
 
Roles of human POLD1 and POLD3 in genome stability
Tumini E, Barroso S, -Calero CP, Aguilera A
Sci Rep 2016 Dec 15;6:38873
PMID 27974823
 
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
 
The human POLD1 gene
Zhao L, Chang LS
Identification of an upstream activator sequence, activation by Sp1 and Sp3, and cell cycle regulation J Biol Chem
PMID 9030545
 

Citation

This paper should be referenced as such :
Domingo E
POLD1 (DNA polymerase delta 1, catalytic subunit);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/POLD1ID41770ch19q13.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(7;19)(p11;q13) EGFR/POLD1


External links

Nomenclature
HGNC (Hugo)POLD1   9175
LRG (Locus Reference Genomic)LRG_785
Cards
AtlasPOLD1ID41770ch19q13.txt
Entrez_Gene (NCBI)POLD1  5424  DNA polymerase delta 1, catalytic subunit
AliasesCDC2; CRCS10; MDPL; POLD
GeneCards (Weizmann)POLD1
Ensembl hg19 (Hinxton)ENSG00000062822 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000062822 [Gene_View]  ENSG00000062822 [Sequence]  chr19:50384323-50418018 [Contig_View]  POLD1 [Vega]
ICGC DataPortalENSG00000062822
TCGA cBioPortalPOLD1
AceView (NCBI)POLD1
Genatlas (Paris)POLD1
WikiGenes5424
SOURCE (Princeton)POLD1
Genetics Home Reference (NIH)POLD1
Genomic and cartography
GoldenPath hg38 (UCSC)POLD1  -     chr19:50384323-50418018 +  19q13.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)POLD1  -     19q13.33   [Description]    (hg19-Feb_2009)
EnsemblPOLD1 - 19q13.33 [CytoView hg19]  POLD1 - 19q13.33 [CytoView hg38]
Mapping of homologs : NCBIPOLD1 [Mapview hg19]  POLD1 [Mapview hg38]
OMIM174761   612591   615381   
Gene and transcription
Genbank (Entrez)AA236879 AB209560 BC008800 BM193218 CD101690
RefSeq transcript (Entrez)NM_001256849 NM_001308632 NM_002691
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)POLD1
Cluster EST : UnigeneHs.279413 [ NCBI ]
CGAP (NCI)Hs.279413
Alternative Splicing GalleryENSG00000062822
Gene ExpressionPOLD1 [ NCBI-GEO ]   POLD1 [ EBI - ARRAY_EXPRESS ]   POLD1 [ SEEK ]   POLD1 [ MEM ]
Gene Expression Viewer (FireBrowse)POLD1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5424
GTEX Portal (Tissue expression)POLD1
Human Protein AtlasENSG00000062822-POLD1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP28340   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP28340  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP28340
Splice isoforms : SwissVarP28340
Catalytic activity : Enzyme2.7.7.7 [ Enzyme-Expasy ]   2.7.7.72.7.7.7 [ IntEnz-EBI ]   2.7.7.7 [ BRENDA ]   2.7.7.7 [ KEGG ]   
PhosPhoSitePlusP28340
Domaine pattern : Prosite (Expaxy)DNA_POLYMERASE_B (PS00116)   
Domains : Interpro (EBI)DNA-dir_DNA_pol_B    DNA-dir_DNA_pol_B_CS    DNA-dir_DNA_pol_B_exonuc    DNA-dir_DNA_pol_B_multi_dom    DNA_pol_palm_dom_sf    RNaseH-like_sf    RNaseH_sf    Znf-C4pol   
Domain families : Pfam (Sanger)DNA_pol_B (PF00136)    DNA_pol_B_exo1 (PF03104)    zf-C4pol (PF14260)   
Domain families : Pfam (NCBI)pfam00136    pfam03104    pfam14260   
Domain families : Smart (EMBL)POLBc (SM00486)  
Conserved Domain (NCBI)POLD1
DMDM Disease mutations5424
Blocks (Seattle)POLD1
SuperfamilyP28340
Human Protein Atlas [tissue]ENSG00000062822-POLD1 [tissue]
Peptide AtlasP28340
HPRD08882
IPIIPI00002894   IPI00655631   IPI00556021   
Protein Interaction databases
DIP (DOE-UCLA)P28340
IntAct (EBI)P28340
FunCoupENSG00000062822
BioGRIDPOLD1
STRING (EMBL)POLD1
ZODIACPOLD1
Ontologies - Pathways
QuickGOP28340
Ontology : AmiGOnucleotide-excision repair complex  nucleotide binding  telomere maintenance  DNA synthesis involved in DNA repair  DNA synthesis involved in DNA repair  nuclear chromosome, telomeric region  DNA binding  chromatin binding  damaged DNA binding  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA replication  DNA-dependent DNA replication  DNA repair  transcription-coupled nucleotide-excision repair  base-excision repair, gap-filling  base-excision repair, gap-filling  nucleotide-excision repair, DNA incision, 5'-to lesion  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  3'-5'-exodeoxyribonuclease activity  response to UV  membrane  aggresome  translesion synthesis  telomere maintenance via semi-conservative replication  nucleotide-excision repair, DNA incision  cellular response to UV  DNA damage response, detection of DNA damage  delta DNA polymerase complex  DNA replication proofreading  metal ion binding  4 iron, 4 sulfur cluster binding  fatty acid homeostasis  
Ontology : EGO-EBInucleotide-excision repair complex  nucleotide binding  telomere maintenance  DNA synthesis involved in DNA repair  DNA synthesis involved in DNA repair  nuclear chromosome, telomeric region  DNA binding  chromatin binding  damaged DNA binding  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  DNA-directed DNA polymerase activity  protein binding  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA replication  DNA-dependent DNA replication  DNA repair  transcription-coupled nucleotide-excision repair  base-excision repair, gap-filling  base-excision repair, gap-filling  nucleotide-excision repair, DNA incision, 5'-to lesion  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  nucleotide-excision repair, DNA gap filling  3'-5'-exodeoxyribonuclease activity  response to UV  membrane  aggresome  translesion synthesis  telomere maintenance via semi-conservative replication  nucleotide-excision repair, DNA incision  cellular response to UV  DNA damage response, detection of DNA damage  delta DNA polymerase complex  DNA replication proofreading  metal ion binding  4 iron, 4 sulfur cluster binding  fatty acid homeostasis  
Pathways : KEGGPurine metabolism    Pyrimidine metabolism    DNA replication    Base excision repair    Nucleotide excision repair    Mismatch repair    Homologous recombination    HTLV-I infection   
REACTOMEP28340 [protein]
REACTOME PathwaysR-HSA-69183 [pathway]   
NDEx NetworkPOLD1
Atlas of Cancer Signalling NetworkPOLD1
Wikipedia pathwaysPOLD1
Orthology - Evolution
OrthoDB5424
GeneTree (enSembl)ENSG00000062822
Phylogenetic Trees/Animal Genes : TreeFamPOLD1
HOVERGENP28340
HOGENOMP28340
Homologs : HomoloGenePOLD1
Homology/Alignments : Family Browser (UCSC)POLD1
Gene fusions - Rearrangements
Fusion : MitelmanEGFR/POLD1 [7p11.2/19q13.33]  [t(7;19)(p11;q13)]  
Fusion : QuiverPOLD1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPOLD1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)POLD1
dbVarPOLD1
ClinVarPOLD1
1000_GenomesPOLD1 
Exome Variant ServerPOLD1
ExAC (Exome Aggregation Consortium)ENSG00000062822
GNOMAD BrowserENSG00000062822
Varsome BrowserPOLD1
Genetic variants : HAPMAP5424
Genomic Variants (DGV)POLD1 [DGVbeta]
DECIPHERPOLD1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPOLD1 
Mutations
ICGC Data PortalPOLD1 
TCGA Data PortalPOLD1 
Broad Tumor PortalPOLD1
OASIS PortalPOLD1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPOLD1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPOLD1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch POLD1
DgiDB (Drug Gene Interaction Database)POLD1
DoCM (Curated mutations)POLD1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)POLD1 (select a term)
intoGenPOLD1
NCG5 (London)POLD1
Cancer3DPOLD1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM174761    612591    615381   
Orphanet22331    23548   
DisGeNETPOLD1
MedgenPOLD1
Genetic Testing Registry POLD1
NextProtP28340 [Medical]
TSGene5424
GENETestsPOLD1
Target ValidationPOLD1
Huge Navigator POLD1 [HugePedia]
snp3D : Map Gene to Disease5424
BioCentury BCIQPOLD1
ClinGenPOLD1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5424
Chemical/Pharm GKB GenePA33496
Clinical trialPOLD1
Miscellaneous
canSAR (ICR)POLD1 (select the gene name)
Probes
Litterature
PubMed134 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePOLD1
EVEXPOLD1
GoPubMedPOLD1
iHOPPOLD1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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