I-SITE 2021 - ANASTASIA - Alternative nucleic acid structures stabilization triggers replicative stress and induces apoptosis


Beyond the double helix of DNA (a.k.a. Watson-Crick duplex), it is now accepted that DNA can transiently fold into higher-order structures comprising not two but three (e.g., triplex DNA, three-way DNA junction) or four strands (e.g., quadruplex DNA, four-way DNA junction). This folding is made possible during DNA transactions (replication, transcription), as a result of torsional stress and local strand separation. These alternative structures might act as roadblocks to polymerases in charge of DNA transactions, which is recognized as a DNA damage. Stabilizing these structures with suited ligands thus represents a new way to foster genetic instability, notably in cells with a flawed repertoire of DNA damage signaling and repair mechanisms (i.e., cancer cells). Here, we studied specific three-way DNA junction ligands to use them either as standalone anticancer agents or in combination with clinically relevant DDR inhibitors in an approach referred to as synthetic lethality strategy

Related references :

Duskova et al., J. Med. Chem. 2019

Duskova et al., J. Am. Chem. Soc. 2020

Zell et al., Nucleic Acids Res. 2021