| Written | 2018-05 | Enric 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 |
| Identity |
| Alias_names | POLD |
| 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
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| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Mar 21 16:32:59 CET 2019 |
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