Understanding mutagenesis by endogenous DNA damage

Juan Garaycoechea began his scientific career in Argentina, where in 2010 he obtained a first-class degree in Biotechnology from Universidad Nacional de Quilmes. He was then awarded the César Milstein scholarship to carry out his PhD studies at the MRC Laboratory of Molecular Biology (LMB), in Cambridge, UK. At the end of his studies, Juan was awarded a Junior Research Fellowship by King’s College, Cambridge to support his post-doctoral research at the LMB. He is a group leader at the Hubrecht Institute from October 2018, where he studies the metabolites that damage DNA and how this leads to mutation in a physiological context.

Understanding mutagenesis by endogenous DNA damage

Knowledge of mutational patterns has expanded significantly, but a persistent challenge is to link these complex patterns to the underlying molecular mechanism or source of DNA damage, especially when that damage is endogenous and not driven by environmental mutagens. Technological advances now allow us to catalogue mutation across tissues or even closely related cell types, but the results are largely descriptive until we identify the endogenous sources of mutation and how they differ across tissues. We combine mouse genetics, advanced sequencing, biochemistry and mass spectrometry to provide a detailed mechanistic understanding of endogenous mutagenesis. We reveal that endogenous guanine adducts are significant drivers of tissue-specific mutagenesis, while the interwoven actions of DNA polymerase Polk and DNA repair mechanisms are pivotal in mitigating mutagenesis. Finally, we use untargeted DNA adductomics to characterize new sources of endogenous DNA damage. Together, our findings shed light on the nature of endogenous DNA damage and the intimate link between the DNA repair and damage tolerance pathways that limit mutagenesis in tissues.