Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication Journal Article
| Authors: | Shinbrot, E.; Henninger, E. E.; Weinhold, N.; Covington, K. R.; Goksenin, A. Y.; Schultz, N.; Chao, H.; Doddapaneni, H.; Muzny, D. M.; Gibbs, R. A.; Sander, C.; Pursell, Z. F.; Wheeler, D. A. |
| Article Title: | Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication |
| 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. |
| Keywords: | endometrioid carcinoma; germline; mismatch repair; mutations; colorectal-cancer; domain; cells; structural basis; delta; high-fidelity; unique error signature |
| Journal Title: | Genome Research |
| Volume: | 24 |
| Issue: | 11 |
| ISSN: | 1088-9051 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2014-11-01 |
| Start Page: | 1740 |
| End Page: | 1750 |
| Language: | English |
| ACCESSION: | WOS:000344442000003 |
| DOI: | 10.1101/gr.174789.114 |
| PROVIDER: | wos |
| PMCID: | PMC4216916 |
| PUBMED: | 25228659 |
| Notes: | Article -- Source: Wos |
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