Li Tonia T, D'Amico Alexandra, Christensen Laura, Vasquez Karen M
Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA.
Genes (Basel). 2025 Aug 11;16(8):942. doi: 10.3390/genes16080942.
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.
重复DNA序列在基因组中大量存在，并可形成替代DNA结构（即非B型DNA）。其中一种结构，Z-DNA，已被证明会在包括人类细胞和小鼠在内的多种生物体中引发基因不稳定。形成Z-DNA的序列在人类癌症基因组的突变热点处富集，这表明它们与癌症病因有关。衰老已知是癌症发生的一个风险因素，而基因不稳定是衰老和癌症的一个标志。然而，衰老如何影响Z-DNA的诱变潜力尚未得到研究。在这里，我们使用转基因小鼠模型探索了衰老对Z-DNA诱变过程的影响。令人惊讶的是，随着年龄增长，Z-DNA诱导的突变减少或保持不变。Z-DNA的切割不受年龄增长的影响，这表明下游修复过程，如双链断裂修复过程，可能参与了小鼠中与年龄相关的Z-DNA诱导诱变变化。
