Exonuclease mutations In DNA Polymerase Epsilon reveal replication strand specific mutation patterns and human origins of replication
- Eve Shinbrot1,
- Erin E. Henninger2,
- Nils Weinhold3,
- Kyle R. Covington1,
- A. Yasemin Göksenin2,
- Nikolaus Schultz3,
- Hsu Chao1,
- HarshaVardhan Doddapaneni1,
- Donna M. Muzny1,
- Richard A. Gibbs1,
- Chris Sander3,
- Zachary F. Pursell2 and
- David A. Wheeler1,4
- 1 Baylor College of Medicine;
- 2 Tulane University School of Medicine;
- 3 Memorial Sloan Kettering Cancer Center
- ↵* Corresponding author; email: wheeler{at}bcm.tmc.edu
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/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 non-functional. 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.
- Received March 3, 2014.
- Accepted September 11, 2014.
- Published by Cold Spring Harbor Laboratory Press
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