Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Short Communication

POLD1 (DNA polymerase delta 1, catalytic subunit) Enric Domingo Department of Oncology, University of Oxford, Oxford, United Kingdom / [email protected]

Published in Atlas Database: May 2018 Online updated version : http://AtlasGeneticsOncology.org/Genes/POLD1ID41770ch19q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69822/05-2018-POLD1ID41770ch19q13.pdf DOI: 10.4267/2042/69822 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Protein Review on POLD1, with data on DNA, on the Description protein encoded, and where the gene is implicated. The POLD1 gene encodes for p125 which is one of Keywords the four subunits that form Polδ (DNA polymerase POLD1; DNA repair; DNA replication; DNA delta) together with POLD2, POLD3 and POLD4 replicase genes. This protein is one of the main DNA replicases in eukaryotes and is responsible of the Identity replication of the lagging strand. POLD1 contains both the catalytic active site and the proofreading Other names: POLD exonuclease domain (residues 245-571). HGNC (Hugo): POLD1 Accordingly, the POLD1 gene confers to Polδ both Location: 19q13.33 replicative and 3' to 5' repair capabilities for the Local order new strand. 50,384,339-50,418,014 Expression DNA/RNA Broadly expressed. Localisation Description Nuclear. POLD1 gene is 33.7 kb long and composed of 1 Function non-coding exon followed by 25 coding exons and one last exon with both coding and 3' UTR regions. Polδ is responsible of the polymerization of the lagging strand during DNA replication in yeast and Transcription humans. It also possesses 3' to 5' exonuclease The length of the transcript is 3444 bp and results in capability to repair missincorporated nucleotides a protein of 1107 residues. during DNA replication. Polδ is also involved in DNA repair pathways such as mismatch repair Pseudogene (MMR), base excision repair (BER), nucleotide There is a pseudogene in chr 6q13 excision repair (NER) or double-strand break (LOC100422453). repair.

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(2) 32 POLD1 (DNA polymerase delta 1, catalytic subunit) Domingo E

Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer Mutations MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Germinal Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini A few missense germline mutations in the S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang proofreading domain of POLD1 have been shown A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson to be pathogenic such as D316G/H, P327L, M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, R409W, L474P or S478N. These are extremely rare Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A. Comprehensive Analysis of in the population and affect the exonuclease repair Hypermutation in Human Cancer. Cell. 2017 Nov of Polδ hence resulting in a mutation rate increase 16;171(5):1042-1056.e10 of about 100-fold. Accordingly, these tumours are Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, usually called ultramutated. Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV, Kaur K, Taylor J, Tomlinson IP. DNA polymerase ε Somatic and δ exonuclease domain mutations in endometrial Although some somatic mutations in POLD1 have cancer. Hum Mol Genet. 2013 Jul 15;22(14):2820-8 been reported for different tumour types, most of Heitzer E, Tomlinson I. Replicative DNA polymerase them are very likely to be passengers. They are mutations in cancer. Curr Opin Genet Dev. 2014 usually found either in non-hypermutated tumours Feb;24:107-13 or in hypermutated tumours due to mismatch repair Nicolas E, Golemis EA, Arora S. POLD1: Central mediator deficiency. So far no POLD1 somatic mutation has of DNA replication and repair, and implication in cancer clearly been shown to be pathogenic. and other pathologies Gene 2016 Sep 15;590(1):128-41 Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Implicated in 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, Proofreading-associated polyposis Humphray S; CORGI Consortium; WGS500 Consortium, (PPAP) Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Disease Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston Autosomal dominant disease with high risk for RS, Tomlinson I. Germline mutations affecting the endometrial carcinoma and/or colorectal adenoma proofreading domains of POLE and POLD1 predispose to or colorectal carcinoma due to germline mutations colorectal adenomas and carcinomas Nat Genet 2013 Feb;45(2):136-44 in POLE or POLD1 genes. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Prognosis Tomlinson I, Church DN. A panoply of errors: polymerase Probably good prognosis in early disease. Although proofreading domain mutations in cancer Nat Rev Cancer not formally proven in POLD1 tumours, 2016 Feb;16(2):71-81 hypermutated tumours due to analog mutations in Tumini E, Barroso S, -Calero CP, Aguilera A. Roles of the polymerase gene POLE that shows a similar human POLD1 and POLD3 in genome stability Sci Rep phenotype are highly immunogenic resulting in 2016 Dec 15;6:38873 better prognosis. In addition, these patients are Valle L, Hernández-Illán E, Bellido F, Aiza G, Castillejo A, likely to respond to immune checkpoint inhibition. 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 References S, Jover R, Lázaro C, Capellá G, Pineda M, Soto JL, Blanco I. New insights into POLE and POLD1 germline Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, mutations in familial colorectal cancer and polyposis Hum Puente DA, Pons T, González S, Iglesias S, Darder E, Mol Genet 2014 Jul 1;23(13):3506-12 Piñol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lázaro C, Capellá G, Puente XS, Valle L. POLE and Zhao L, Chang LS. The human POLD1 gene Identification POLD1 mutations in 529 kindred with familial colorectal of an upstream activator sequence, activation by Sp1 and cancer and/or polyposis: review of reported cases and Sp3, and cell cycle regulation J Biol Chem recommendations for genetic testing and surveillance. Genet Med. 2016 Apr;18(4):325-32 This article should be referenced as such: Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, Domingo E. POLD1 (DNA polymerase delta 1, catalytic de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, subunit). Atlas Genet Cytogenet Oncol Haematol. 2019; Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, 23(2):32-33.

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