Z-DNA at the crossroads: untangling its role in genome dynamics

DNA can fold into noncanonical left-handed Z-DNA conformation beyond the right-handed B-DNA. While its crystal structure was discovered nearly four decades ago, it was predominantly considered a structural curiosity. Recent evidence suggests that Z-DNA formation occurs in nuclear and mitochondrial DNA (mtDNA), with significant biological implications. However, our understanding of its roles remains in its infancy, primarily due to a lack of study tools. In this review we summarize the structure and function of Z-DNA within the genome while addressing the difficulties associated with identifying and investigating its role(s). We then critically evaluate several intracellular factors that can modulate and regulate Z-DNA. Additionally, we discuss the recent technological and methodological advances that may overcome the challenges and enhance our understanding of Z-DNA.