In certain contexts, DNA – especially in guanine-rich regions – can twist itself into entirely different architectures such as G-quadruplexes (G4s), four-stranded structures stabilized by planar arrangements of guanine bases, called G-quartets. G4s can play essential roles in gene regulation processes, but may also have a role in one of DNA’s greatest challenges: oxidative damage.
Incorporation of oxidized lesions into a dsDNA model system promotes formation of kinetically-trapped G-quadruplexes. [from Aleksič S. et al. (2025) Nucleic Acids Research 53(6)]Guanine is unique among DNA bases because it combines two properties of particular biological importance; its ability to associate into G-quartets and G4 structures, and its high susceptibility to oxidation. The interplay between these two features is crucial for genome stability and regulation. Under oxidative stress, guanine can be converted into 8-oxoguanine and later enzymatically cleaved, yielding abasic sites. The structural and functional outcome of these modifications depends strongly on their position within a G4-forming sequence: at some sites, the damaged base can still participate in the planar G-quartet, whereas at others it disrupts G4 folding entirely, shifting the equilibrium between duplex DNA and G-quadruplex structures. Interestingly, many regulatory DNA regions contain “backup” G-tracts that enable damaged guanines to be bypassed, thus helping preserve the G4 fold even under oxidative conditions. To better understand how oxidative damage destabilizes duplex DNA while promoting G-quadruplex formation, CERIC PhD student Simon Aleksič, his supervisor Dr Peter Podbevšek, and Prof. Janez Plavec investigated model systems consisting of a G-rich strand with an incorporated oxidized lesion, and its complementary C-rich strand. Using the DAVID, ASKA, and LARA spectrometers at the SloNMR, CERIC Slovenian Partner Facility, they showed that G4 structures could still form thanks to the presence of backup G-tracts. However, most of these structures represented kinetically trapped intermediates – sufficiently stable to persist transiently, but not necessarily the thermodynamically preferred state compared to duplex DNA.
By uncovering how G4s respond to oxidative damage – and how backup G-tracts rescue their function – scientists gain new insights into how cells and their biomacromolecular constituents face oxidative stress.
