ABSTRACT 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.
Mandke et al. (Tue,) studied this question.