Des outils moléculaires toujours plus multifonctionnels pour l’étude de structures alternatives d’acides nucléiques.

G-Quadruplexes (G4) are non-canonical secondary structure found throughout the genome and transcriptome in guanine rich sequences. Their involvement in biologically relevant processes (telomeres maintenance, transcription and translation) has been demonstrated, yet their role is still not fully elucidated. To investigate their role, we focus on the development of biomimetic molecular tools that could be used either to isolate G4 by new generation sequencing techniques or visualize them directly in cell. This class of molecular tools (TASQ: Template Assembled Synthetic Quartet) is composed by four guanine moieties linked to a central template thanks to spacers of different chemical nature. I…

Biomimetic G-quartet compounds

DNA folds threaten genetic stability and can be leveraged for chemotherapy

International audience; Damaging DNA is a current and efficient strategy to fight against cancer cell proliferation. Numerous mechanisms exist to counteract DNA damage, collectively referred to as the DNA damage response (DDR) and which are commonly dysregulated in cancer cells. Precise knowledge of these mechanisms is necessary to optimise chemotherapeutic DNA targeting. New research on DDR has uncovered a series of promising therapeutic targets, proteins and nucleic acids, with application notably via an approach referred to as combination therapy or combinatorial synthetic lethality. In this review, we summarise the cornerstone discoveries which gave way to the DNA being considered as an…

How to untie G-quadruplex knots and why?

International audience; For over two decades, the prime objective of the chemical biology community studying G-quadruplexes (G4s) has been to use chemicals to interact with and stabilize G4s in cells to obtain mechanistic interpretations. This strategy has been undoubtedly successful, as demonstrated by recent advances. However, these insights have also led to a fundamental rethinking of G4-targeting strategies: due to the prevalence of G4s in the human genome, transcriptome, and ncRNAome (collectively referred to as the G4ome), and their involvement in human diseases, should we continue developing G4-stabilizing ligands or should we invest in designing molecular tools to unfold G4s? Here, …