Fishing G4-interacting proteins

One of the major challenges to explore G4 functions in cells and to design specific ligands is their intrinsic polymorphic structure. In the framework of a collaborative project funded by ANR (G4-TopIPro), we used chemically constrained G4 structures to stabilize a particular G4 DNA or RNA topology as baits to fish G4-interacting proteins. This allowed us to identify new G4-interacting proteins, such as the NELF complex involved in the RNA-Pol II pausing mechanism. NELF complex and RNA Pol II pausing favour DNA double-strand break induction following G4 stabilization by Pyridostatin (doi: 10.1038/s41598-021-92806-8). In addition, we found that DNA topoisomerases play major roles in the cytotoxicity induced by G4 ligands (Pyridostatin and CX5461) during transcription. TOP2A and transcription favour the clastogenic activity of these ligands, while TOP1 that limits transcriptional G4 formation repress their activity. We propose that these G4 ligands also act as DNA structure-driven TOP2 poison at transcribed regions bearing G4 structures (doi: 10.7554/eLife.65184).