Triplex H-DNA Structure: The Long and Winding Road from the Discovery to Its Role in Human Disease
Julia A. Hisey, Chiara Masnovo, Sergei M. Mirkin
Abstract
Abstract H-DNA is an intramolecular DNA triplex formed by homopurine-homopyrimidine mirror repeats. Since its discovery, the field has advanced from characterizing the structure in vitro to discovering its existence and role in vivo. H-DNA interacts with cellular machinery in unique ways, stalling DNA and RNA polymerases and causing genome. The foundational S1 nuclease and chemical probing technologies originally used to show H-DNA formation have been updated and combined with genome-wide sequencing methods for large-scale mapping of secondary structures. There is evidence for triplex H-DNA’s role in polycystic kidney disease, cancer, and numerous repeat expansion diseases. In polycystic kidney disease (PKD), an H-DNA forming repeat region within the PKD1 gene stalls DNA replication and induces fragility. H-DNA- forming repeats in various genes have a role in cancer; the most well-studied examples involve H-DNA-mediated fragility causing translocations in multiple lymphomas. Lastly, H-DNA-forming repeats have been implicated in four repeat expansion diseases: Friedreich's ataxia (FRDA), GAA-FGF14-related ataxia, X-linked Dystonia Parkinsonism (XDP), and cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). In this review, we summarize H-DNA’s discovery and characterization, evidence for its existence and function in vivo, and the field's current knowledge on its role in physiology and pathology.