Dehydration-Responsive Left-Handed G-Quadruplexes Expandthe Sequence Repertoire

Chen, Y.; Hendrickson, A.; Gros, J.; Xing, E.; Windle, E. R.; Wang, J.; Edkins, R. M.; Quinn, S. J.; Yatsunyk, L. A.; Mergny, J.-L.

doi:10.64898/2026.10.05.756892

bioRxiv · 10.64898/2026.10.05.756892

Dehydration-Responsive Left-Handed G-Quadruplexes Expandthe Sequence Repertoire

Chen, Y.·Hendrickson, A.·Gros, J.·Xing, E.·Windle, E. R.·Wang, J.·Edkins, R. M.·Quinn, S. J.·Yatsunyk, L. A.·Mergny, J.-L.

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Abstract

G-quadruplexes (G4s) are widely studied noncanonical nucleic-acid structures that carry important biological functions. Typically, G4s form from G-rich sequences containing at least four tracts of more than two consecutive guanines, yet a plethora of unconventional G4-forming sequences have been identified, including sequences that fold into G4s only under specific conditions. These G4 states remain poorly resolved. Here we identify dehydration-responsive left-handed G4s (drLHG4s), a class of left-handed G4 (LHG4) structures accessible under dehydrating conditions. Using d(GT)n repeats, we show that left-handed folding depends on repeat length, salt condition and solvent conditions. Systematic mutational analysis reveals a broader but register-constrained sequence space, while high-resolution crystal structures of d-GTGGTGTGTGGTG, a sequence that folded robustly under dehydrating conditions, establish a bulged LHG4 architecture and reveal a distinctive hydration sphere. We further show that selected peptides and a cationic zinc phthalocyanine derivative, ZnTEGQPyrPc, containing four triethylene glycol methyl ether tails can induce LHG4 states. Together, our findings reveal a dehydration-responsive G4 landscape and expand the experimentally accessible sequence space of LHG4 folding.

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Chen, Y., Hendrickson, A., Gros, J., Xing, E., Windle, E. R., Wang, J., Edkins, R. M., Quinn, S. J., Yatsunyk, L. A., Mergny, J.-L.. 2026-10-14. Dehydration-Responsive Left-Handed G-Quadruplexes Expandthe Sequence Repertoire. https://doi.org/10.64898/2026.10.05.756892

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