Formation and biological implications of Z-DNA

Z-DNA is a left-handed alternative DNA structure that forms at alternating purine-pyrimidine repeats, which are abundant in genomes. It is intrinsically unstable under physiological conditions; however, it can be stabilized by negative supercoiling and specific Z-DNA binding proteins. These stabilizing factors have prompted renewed interest in the biological significance of Z-DNA within the genome. Emerging evidence suggests that Z-DNA plays critical roles in various cellular processes, including transcriptional regulation, genome instability, chromatin remodeling, and the development of human diseases. This review summarizes existing methodologies for local and global identification of Z-DNA, its genomic and epigenetic features, the factors influencing its formation and stability, its biological implications, and future directions to advance our understanding of Z-DNA biology and its potential applications.