Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polk and DNA repair

Knowledge of mutational patterns has expanded significantly, but a persistent challenge is to link these complex patterns to the underlying molecular mechanism, especially when DNA damage is endogenous and not driven by environmental mutagens. Technological advances now allow us to catalogue mutation across tissues or cell types, but the results are largely descriptive until we identify the endogenous sources of mutation and how they differ across tissues. Here, we combine mouse genetics, sequencing, biochemistry and mass spectrometry to provide a detailed mechanistic understanding of endogenous mutagenesis. We reveal that endogenous guanine adducts drive tissue-specific mutagenesis, while the interwoven actions of DNA polymerase Polk and DNA repair mechanisms are pivotal in mitigating mutagenesis. For the first time, we use untargeted DNA adductomics to characterize new sources of endogenous DNA damage. Our novel approach to understanding endogenous mutational landscapes reveals previously unseen mutational processes and points to vast potential for new discoveries.