Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

ELife
Karl P HodelZachary F Pursell

Abstract

Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε.

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Citations

Feb 16, 2020·Nature Genetics·Masayuki NakamoriChristopher E Pearson
Dec 21, 2019·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Maja HühnsFriedrich Prall
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Oct 16, 2021·Current Opinion in Oncology·Diego ProstMehdi Touat

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Datasets Mentioned

BETA
PRJNA327240

Methods Mentioned

BETA
PCR
exome sequencing
single-cell sequencing

Software Mentioned

learn Python
ANNOVAR
R package
MEM
Scikit
BWA
MuTect
cBioPortal
Genome Analysis Toolkit ( GATK )

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