A Chemoptogenetic Tool for Spatiotemporal Induction of Oxidative DNA Lesions In Vivo

Oxidative nuclear DNA damage increases in all tissues with age in multiple animal models, as well as in humans. However, the increase in DNA oxidation varies from tissue to tissue, suggesting that certain cells/tissues may be more vulnerable to DNA damage than others. The lack of a tool that can control dosage and spatiotemporal induction of oxidative DNA damage, which accumulates with age, has severely limited our ability to understand how DNA damage drives aging and age-related diseases. To overcome this, here we developed a chemoptogenetic tool that produces 8-oxoguanine (8-oxoG) at DNA in a whole organism, Caenorhabditis elegans. This tool uses di-iodinated malachite green (MG-2I) photosensitizer dye that generates singlet oxygen, ¹O₂, upon fluorogen activating peptide (FAP) binding and excitation with far-red light. Using our chemoptogenetic tool, we are able to control generation of singlet oxygen ubiquitously or in a tissue-specific manner, including in neurons and muscle cells. To induce oxidative DNA damage, we targeted our chemoptogenetic tool to histone, his-72, that is expressed in all cell types. Our results show that a single exposure to dye and light is able to induce DNA damage, promote embryonic lethality, lead to developmental delay, and significantly reduce lifespan. Our chemoptogenetic tool will now allow us to assess the cell autonomous versus non-cell autonomous role of DNA damage in aging, at an organismal level.