Despite common confusion among the general public, scientific disseminators, and even some scientists, the DNA double helix is right-handed… or maybe not?

The classical structure of DNA is a two-stranded, right-handed helix, meaning its rotation follows a clockwise direction. However, it has long been observed that certain DNA sequences can form helices with a left-handed, counter-clockwise rotation. These helices are not mirror images of classical DNA but have a different shape known as Z-DNA. Z-DNA formation occurs only in sequences rich in CG repeats and typically requires extremely high salt concentrations. Yet, certain proteins can induce the formation of these structures within cells under physiological conditions. Interestingly, some of these proteins are involved in regulating the immune response, and in cancer cells, their binding to Z-DNA is thought to help these cells evade the immune system.

Within our studies on chemically modified DNAs, also known as ‘Xeno Nucleic Acids’ or XNAs, we have observed that introducing fluorine atoms in specific key positions of the DNA sugar chain induces the formation of Z-DNA under entirely physiological conditions. This apparently minimal modification results in a radical change in the direction of the double helix’s rotation. These fluorinated XNAs are recognized by Z-DNA binding proteins, potentially altering their activity. Moreover, the fluorine nucleus is magnetically active and can be easily detected using Nuclear Magnetic Resonance (NMR) techniques, paving the way for detecting left-handed DNA both in vitro and in vivo.

This work has been carried out through a long-standing collaboration with Prof. Masad Damha’s group at McGill University in Montreal (Canada) and Prof. Modesto Orozco’s group at the IRB (Barcelona). The use of Nuclear Magnetic Resonance (NMR) spectrometers from the ‘Manuel Rico’ Laboratory, a unique scientific-technical facility (ICTS) of the CSIC, has been crucial in this research.

Publication: R. El-Khoury,+ C. Cabrero,+ S. Movilla, H. Kaur, D. Friedland, A. Domínguez, J. D. Thorpe, M. Roman, M. Orozco,* C. González,* M.J. Damha*. Formation of left-handed helices by C2′-fluorinated nucleic acids under physiological salt conditions. Nucleic Acids Res. https://doi.org/10.1093/nar/gkae508