Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.

TitleExonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
Publication TypeJournal Article
Year of Publication2014
AuthorsShinbrot, E, Henninger, EE, Weinhold, N, Covington, KR, A Göksenin, Y, Schultz, N, Chao, H, Doddapaneni, HV, Muzny, DM, Gibbs, RA, Sander, C, Pursell, ZF, Wheeler, DA
JournalGenome Res
Volume24
Issue11
Pagination1740-50
Date Published2014 Nov
ISSN1549-5469
KeywordsAtaxia Telangiectasia Mutated Proteins, Codon, Nonsense, Databases, Genetic, DNA Mutational Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Exonucleases, Genome-Wide Association Study, Humans, Microsatellite Instability, Models, Molecular, Mutation, Missense, Neoplasms, Phosphatidylinositol 3-Kinases, Protein Structure, Tertiary, Replication Origin, Tumor Suppressor Protein p53
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.

DOI10.1101/gr.174789.114
Alternate JournalGenome Res.
PubMed ID25228659
PubMed Central IDPMC4216916
Grant ListU24CA143840 / CA / NCI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
R00 ES016780 / ES / NIEHS NIH HHS / United States
P20 RR020152 / RR / NCRR NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
ES016780 / ES / NIEHS NIH HHS / United States
RR020152 / RR / NCRR NIH HHS / United States