Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication (original) (raw)
- Erin E. Henninger2,5,
- Nils Weinhold3,5,
- Kyle R. Covington1,
- A. Yasemin Göksenin2,
- Nikolaus Schultz3,
- Hsu Chao1,
- HarshaVardhan Doddapaneni1,
- Donna M. Muzny1,
- Richard A. Gibbs1,4,
- Chris Sander3,
- Zachary F. Pursell2 and
- David A. Wheeler1
- 1Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA;
- 3Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
- 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
- Corresponding author: wheeler{at}bcm.edu
- ↵5 These authors contributed equally to this paper.
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.
Footnotes
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.174789.114.
Received March 3, 2014.
Accepted September 11, 2014.
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