Mutations are a permanent record of past chemical and biochemical insults experienced by a cell.  Each time the genome replicates, it accumulates mutations in patterns that reflect: (a) the DNA sequence context-dependent formation of damage; (b) the differential activity of DNA repair proteins, which, depending on the type of lesion, can eliminate, ignore or intensify the mutagenic consequences of the lesion; and (c) the choice of replication machinery that synthesizes the nascent genomic copy. In combination, these three factors produce a richly contoured mutational spectrum that, from appearances, is distinct for most individual forms of DNA damage.  This mutational pattern, if appropriately decoded can reveal the history of genome-altering events such as chemical exposures, pathogen-stimulated base deaminations, metabolic stress, and inflammation, which in turn can provide an indication of the underlying causes and mechanisms of genetic disease.  New tools help us glean a deep mechanistic understanding of the cellular factors and pathways that modulate a mutational process and, in turn, provide opportunities for better diagnostic and prognostic biomarkers, better exposure risk assessment and even actionable therapeutic targets. The goal of this talk is to present a bottom-up, lesion-centric framework of mutagenesis that integrates the contributions of lesion replication, lesion repair and lesion formation to explain the complex mutational spectra that emerge in the genome following exposure to mutagens. The mutational spectra of the well-studied hepatocarcinogen aflatoxin B<sub>1</sub> and several alkylating agents serve as specific examples, but the implications are meant to be generalizable.

Mutational spectra provide insight into the mechanisms bridging DNA damage to genetic disease

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.