Abstract
There is emerging evidence that dysregulation of the epigenome plays a dominant role in organismal decline during aging, but it is uncertain what causes this dysregulation. DNA damage is one possible driver of these epigenetic changes, as induction of DNA damage leads to an accelerated aging of the epigenomes of diverse organisms. However, the most convincing way to test this hypothesis is to evaluate epigenetic changes in model organisms with enhanced DNA repair. Generating such model organisms has proven difficult, because overexpression of endogenous DNA repair proteins often leads to genomic instability, likely due to stoichiometric imbalances in multi-protein DNA repair complexes. We hypothesized that DNA repair proteins from other species (i.e. “exogenous”) wouldn’t lead to this stoichiometric disruption and could improve mammalian genome stability. To identify such proteins, we generated and screened a library comprised of DNA repair genes from polyextremophiles that can survive extremely high levels of DNA damage. This screen identified six genes that more than tripled the viability of human cells exposed to high doses of H2O2. This enhanced survival likely results from improved DNA repair and protection mechanisms, as cells expressing these genes had fewer double-strand breaks following exposure to non-lethal doses of H2O2. We are currently testing if expression of these genes reduces epigenetic alterations following DNA damage, and if expression of these genes in yeast is able to affect epigenetic changes and lifespan. These experiments could provide powerful evidence of a connection between the stability of the genome and epigenome during aging.