TY  - JOUR
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
Y1  - 2014/11/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1740 
EP  - 1750 
DO  - 10.1101/gr.174789.114 
VL  - 24 
IS  - 11 
UR  - http://genome.cshlp.org/content/24/11/1740.abstract 
N2  - 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. 
ER  -