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

E Shinbrot, EE Henninger, N Weinhold… - Genome …, 2014 - genome.cshlp.org
Genome research, 2014genome.cshlp.org
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 …
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.
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