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

Karl P. Hodel, Richard De Borja, Erin E. Henninger, Brittany B. Campbell, Nathan Ungerleider, Nicholas Light, Tong Wu, Kimberly G. Lecompte, A. Yasemin Goksenin, Bruce A. Bunnell, Uri Tabori, Adam Shlien, Zachary F. Pursell

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Abstract

Tumors defective for DNA polymerase (Pol) ɛ proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ɛ 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 ɛ proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ɛ 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 ɛ 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 ɛ.

Original languageEnglish
Article numbere32692
JournaleLife
Volume7
DOIs
StatePublished - 28 Feb 2018

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    Hodel, K. P., De Borja, R., Henninger, E. E., Campbell, B. B., Ungerleider, N., Light, N., Wu, T., Lecompte, K. G., Goksenin, A. Y., Bunnell, B. A., Tabori, U., Shlien, A., & Pursell, Z. F. (2018). Explosive mutation accumulation triggered by heterozygous human Pol ɛ proofreading-deficiency is driven by suppression of mismatch repair. eLife, 7, [e32692]. https://doi.org/10.7554/eLife.32692