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Elucidating the Role of Transcriptional Mutagenesis in the Acquisition of Adaptive Mutations

For nearly a century, we have understood mutagenesis as a growth‐dependent process involving DNA replication. More recently, cells have been shown to accumulate adaptive mutations in response to selective pressure that induces prolonged growth arrest. While multiple mechanisms related to DNA damage and genome maintenance have been shown to contribute, the specific role of DNA base damage and base excision repair in the process has not been explored. Base damage can be bypassed by RNA polymerase, resulting in a pool of mutant mRNAs through transcriptional mutagenesis (TM), and potentially a population of mutant proteins that could alter the phenotype of the cell. In non‐dividing cells, such as those subject to drug pressure, the influence of persistent DNA damage on transcription could affect cellular outcomes. We hypothesize that TM could be an important first step in acquiring drug resistance, as the mutant protein generated could allow cells to resume DNA replication and convert this damage to a permanent advantageous mutation, a process we call retromutagenesis. Using Saccharomyces cerevisiae as a model organism, we have established an experimental system that examines adaptive mutagenesis in response to canavanine exposure. Within this system, we have demonstrated that prolonged exposure to canavanine yields an increase in intracellular reactive oxygen species, and that cells deficient in the repair of the oxidative lesion 8‐oxoguanine (ogg1 knockouts) show an increase in adaptive mutation frequency. Additionally, DNA sequencing of the target gene in adaptive mutants from this repair deficient cell line has revealed a strand bias for the DNA damage leading to canavanine resistance in the template strand related to transcription. These results support our hypothesis that mutagenic transcription past DNA damage in non‐dividing cells could contribute to the mechanism by which adaptive mutations arise.