Garaycoechea: Metabolic mutagenesis

DNA carries the instructions of life, but is also under constant attack. The resulting damage, if not repaired, leads to mutation and disease. Common environmental mutagens include sunlight and cigarette smoke, but the integrity of DNA is also threatened by chemicals produced by our own body. Our group wants to understand what are the metabolites that arise within cells that damage DNA, and the consequences of this damage. Particularly, we are interested in understanding the maintenance of genome stability in stem cells, the rare cell populations responsible for tissue maintenance.

Recent sequencing efforts have revealed that cancer types carry different patterns of mutation, suggesting that what causes the damage or how it is repaired varies from tissue to tissue. Our research will therefore aim to answer fundamental questions relating to the maintenance of genome integrity in a physiological setting: are there tissue-specific mutagenic processes? What are the endogenous metabolites that damage DNA? And what are the DNA repair/tolerance mechanisms that lead to mutagenesis in vivo? Our lab applies tools from the fields of DNA repair and stem cell biology, as well as ESC and organoid culture, genomics and mouse genetics to interrogate these fundamental questions.