Aging Increases Short, Inverted Repeat-Mediated Genomic Instability In Vivo

Genomic instability is a hallmark of aging and cancer. A key contributor to genomic instability includes alternative DNA structures, such as cruciform-forming inverted repeats (IRs). Short IRs (< 100 bps) are abundant in the human genome, mutagenic, and enriched at mutation hotspots in human cancer genomes. Using an innovative mutation-reporter mouse model, we showed that short IRs are mutagenic in vivo. Further, we found that aging exacerbates IR-induced genomic instability, as evidenced by increased mutation frequencies and altered spectra in the spleen and brain of mice harboring either a short IR or control B-DNA sequence at 2 and 24 months of age. These findings establish a link between aging and enhanced mutagenesis at short IRs, providing a unique in vivo platform to investigate age-related mechanisms of DNA structure-mediated genomic instability.