eLife (Feb 2018)

Explosive mutation accumulation triggered by heterozygous human Pol ε 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

DOI
https://doi.org/10.7554/eLife.32692
Journal volume & issue
Vol. 7

Abstract

Read online

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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