I-SITE 2021 - ANASTASIA - Alternative nucleic acid structures stabilization triggers replicative stress and induces apoptosis
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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 |
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Related references : Duskova et al., J. Med. Chem. 2019 |
