Enhanced Genomic Stability and its Effects on Aging and the Epigenome

Abstract

The epigenomes of evolutionarily distant species undergo similar alterations during aging, but the upstream causes of these changes are unclear. DNA damage is one potential cause, as epigenetic changes arising from DNA damage are remarkably similar to those observed during aging. To more definitively test if DNA damage is a cause of age-related epigenetic dysfunction, model organisms with enhanced DNA repair should be used to determine whether improved genomic stability mitigates epigenetic changes during aging. Generating such organisms has proven difficult, due to toxicity from overexpressing endogenous DNA repair proteins. I hypothesized that expressing exogenous DNA repair proteins could would be a more viable strategy for generating multiple model organisms with enhanced genomic stability. In Chapter 2, I identify multiple DNA repair proteins from radioresistant organisms that improve the genomic stability of human fibroblasts exposed to hydrogen peroxide. Two of these proteins- the single-stranded DNA-binding protein SSB and the double-stranded DNA-binding protein Dps1- also enhanced genomic stability in Saccharomyces cerevisiae, with SSB also improving genomic stability in Caenorhabditis elegans. I discovered that SSB improves genomic stability by enhancing the efficiency of non-homologous end joining, while Dps1 likely improves genomic stability by protecting DNA from free radical damage. In Chapter 3, I tested whether SSB and Dps1 could preserve the epigenomes of yeast and worms in response to either DNA damage or aging. Both genes mitigated the loss of silencing at the HMR locus caused by DNA damage, a major epigenetic change that occurs during yeast aging. However, only Dps1 was able to extend yeast replicative lifespan. SSB extends the lifespan of worms while also improving healthspan. I discover that worms undergo a global reduction of histone 3 levels with age and following DNA damage, and show that SSB transgenic worms have a delayed onset of this loss. In Chapter 4, I explore how SSB and Dps1 can be further characterized and utilized in aging research. Taken together, these results suggest that DNA damage is a conserved driver of age-related epigenetic changes, and that enhancing genome stability preserves the aging epigenome.