Under physiological conditions, most double-stranded nucleic acids adopt right-handed helical conformations such as B-DNA or A-RNA. However, under specific cellular stresses, nucleic acids can transition into higher-energy left-handed structures known as Z-form nucleic acids (ZNAs), including Z-DNA and Z-RNA. These structures exhibit alternating syn and anti base conformations and a characteristic zigzag sugar-phosphate backbone, conferring physicochemical properties distinct from those of canonical nucleic acids.
The innate immune sensor ZBP1 (Z-DNA-binding protein 1) recognizes ZNAs and functions as a cellular stress surveillance mechanism that enables cells to detect pathogenic invasion, genome instability, and aberrant nucleic acid metabolism. Since the original discovery of Z-DNA by Alexander Rich and colleagues in 1979, the mechanisms governing ZNA formation under physiological conditions have remained a longstanding question in the field of nucleic acid biology. Although ZNA formation can be stabilized in vitro under extreme conditions such as high salt concentrations or artificial guanine modifications, these settings lack physiological relevance. Recent studies have linked ZNA generation to transcription-induced topological stress, endogenous retrovirus activation, and RNA splicing defects; however, the endogenous molecular driving force responsible for ZNA formation in vivo has remained elusive.
Drug-induced liver injury (DILI) is a leading cause of acute liver failure (ALF), and acetaminophen (APAP) overdose accounts for more than half of ALF cases in Western countries. APAP is metabolized by CYP2E1 into the toxic intermediate NAPQI, which damages mitochondria and triggers a burst of reactive oxygen species (ROS), ultimately leading to catastrophic mitochondrial dysfunction and hepatocyte death. Although N-acetylcysteine (NAC) remains the only approved therapy for APAP overdose, its efficacy declines dramatically after approximately 8 hours post-intoxication, leaving patients with delayed treatment options at high risk of mortality.
In this study, the authors provided the first direct evidence that oxidative base modifications function as an endogenous molecular driving force for DNA conformational switching from B-DNA to Z-DNA in vivo. Using chemically oxidized dGdC DNA sequences, they demonstrated that guanine oxidation alone was sufficient to induce a dramatic structural transition from the canonical B-form into the left-handed Z-form.
doi:10.15302/vita.2026.04.0029