Title | Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Shinbrot, E, Henninger, EE, Weinhold, N, Covington, KR, A Göksenin, Y, Schultz, N, Chao, H, Doddapaneni, H, Muzny, DM, Gibbs, RA, Sander, C, Pursell, ZF, Wheeler, DA |
Journal | Genome Res |
Volume | 24 |
Issue | 11 |
Pagination | 1740-50 |
Date Published | 2014 Nov |
ISSN | 1549-5469 |
Keywords | Ataxia Telangiectasia Mutated Proteins, Class Ia Phosphatidylinositol 3-Kinase, Codon, Nonsense, Databases, Genetic, DNA Mutational Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Exonucleases, Genome-Wide Association Study, Humans, Microsatellite Instability, Models, Molecular, Mutation, Missense, Neoplasms, Phosphatidylinositol 3-Kinases, Protein Structure, Tertiary, Replication Origin, Tumor Suppressor Protein p53 |
Abstract | Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication. |
DOI | 10.1101/gr.174789.114 |
Alternate Journal | Genome Res |
PubMed ID | 25228659 |
PubMed Central ID | PMC4216916 |
Grant List | U24CA143840 / CA / NCI NIH HHS / United States U54HG003273 / HG / NHGRI NIH HHS / United States R00 ES016780 / ES / NIEHS NIH HHS / United States P20 RR020152 / RR / NCRR NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States U24 CA143840 / CA / NCI NIH HHS / United States U24 CA143843 / CA / NCI NIH HHS / United States ES016780 / ES / NIEHS NIH HHS / United States RR020152 / RR / NCRR NIH HHS / United States |
Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
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