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 language | English |
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Article number | e32692 |
Journal | eLife |
Volume | 7 |
DOIs | |
State | Published - 28 Feb 2018 |