RT Journal
A1 Shinbrot, Eve
A1 Henninger, Erin E.
A1 Weinhold, Nils
A1 Covington, Kyle R.
A1 Göksenin, A. Yasemin
A1 Schultz, Nikolaus
A1 Chao, Hsu
A1 Doddapaneni, HarshaVardhan
A1 Muzny, Donna M.
A1 Gibbs, Richard A.
A1 Sander, Chris
A1 Pursell, Zachary F.
A1 Wheeler, David A.
T1 Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication
JF Genome Research 
JO Genome Research 
YR 2014 
FD November 01 
VO 24 
IS 11 
SP 1740 
OP 1750 
DO 10.1101/gr.174789.114 
UL http://genome.cshlp.org/content/24/11/1740.abstract 
AB 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.