Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast

Abstract

Significance Cancer cells often have defects in DNA repair and are killed effectively by drugs that damage DNA. However, surviving cells can acquire additional mutations after treatment with these genotoxic chemicals. Here we apply a simple model system to reveal synergy between specific DNA repair mutations and genotoxic drugs that occurs independently of fitness defects. Moreover, by analyzing the entire genome of a mutagenized cell population, we identify a signature of mutations that informs the mechanism of the translesion synthesis DNA damage tolerance pathway. Our work establishes a conceptual framework for predicting the mutational burden of cells surviving genotoxin treatment and adds to a growing list of examples supporting the utility of model organism mutation signature analysis for generating mechanistic insights.