Effects of Aging on Z-DNA-Induced Genetic Instability In Vivo

Repetitive DNA sequences are abundant in genomes and can adopt alternative DNA structures (i.e., non-B DNA). One such structure, Z-DNA, has been shown to stimulate genetic instability in a variety of organisms, including human cells and mice. Z-DNA-forming sequences are enriched at mutation hotspots in human cancer genomes, implicating them in cancer etiology. Aging is a known risk factor for the development of cancer, and genetic instability is a hallmark of both aging and cancer. However, how aging affects the mutagenic potential of Z-DNA has not yet been investigated. Here, we explored the effects of aging on the mutagenic processing of Z-DNA using a transgenic mouse model. Surprisingly, Z-DNA-induced mutations decreased or remained unchanged with increasing age. Cleavage of Z-DNA was unaffected with increasing age, suggesting that downstream repair processing, such as double-strand break repair processes, may be involved in the age-related changes in Z-DNA-induced mutagenesis in mice.