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.
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Authors | Eve Shinbrot, Erin E Henninger, Nils Weinhold, Kyle R Covington, A Yasemin Göksenin, Nikolaus Schultz, Hsu Chao, HarshaVardhan Doddapaneni, Donna M Muzny, Richard A Gibbs, Chris Sander, Zachary F Pursell, David A Wheeler |
Journal | Genome research
(Genome Res)
Vol. 24
Issue 11
Pg. 1740-50
(Nov 2014)
ISSN: 1549-5469 [Electronic] United States |
PMID | 25228659
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Published by Cold Spring Harbor Laboratory Press. |
Chemical References |
- Codon, Nonsense
- Tumor Suppressor Protein p53
- PIK3R1 protein, human
- Class Ia Phosphatidylinositol 3-Kinase
- ATM protein, human
- Ataxia Telangiectasia Mutated Proteins
- POLD1 protein, human
- DNA Polymerase II
- DNA Polymerase III
- Exonucleases
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Topics |
- Ataxia Telangiectasia Mutated Proteins
(genetics, metabolism)
- Class Ia Phosphatidylinositol 3-Kinase
- Codon, Nonsense
- DNA Mutational Analysis
- DNA Polymerase II
(chemistry, genetics, metabolism)
- DNA Polymerase III
(genetics, metabolism)
- DNA Replication
- Databases, Genetic
- Exonucleases
(chemistry, genetics, metabolism)
- Genome-Wide Association Study
- Humans
- Microsatellite Instability
- Models, Molecular
- Mutation, Missense
- Neoplasms
(enzymology, genetics, metabolism)
- Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Protein Structure, Tertiary
- Replication Origin
(genetics)
- Tumor Suppressor Protein p53
(genetics, metabolism)
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