Guanine-quadruplex structures (G4) are unusual nucleic acid conformations formed by guanine-rich DNA and RNA sequences and known to control gene expression mechanisms, from transcription to protein synthesis. So far, a number of molecules that recognize G4 have been developed for potential therapeutic applications in human pathologies, including cancer and infectious diseases. These molecules are called G4 ligands. When the biological effects of G4 ligands are studied, the analysis is often limited to nucleic acid targets. However, recent evidence indicates that G4 ligands may target other cellular components and compartments such as lysosomes and mitochondria. Here, we summarize our current knowledge of the regulation of lysosome by G4 ligands, underlying their potential functional impact on lysosome biology and autophagic flux, as well as on the transcriptional regulation of lysosomal genes. We outline the consequences of these effects on cell fate decisions and we systematically analyzed G4-prone sequences within the promoter of 435 lysosome-related genes. Finally, we propose some hypotheses about the mechanisms involved in the regulation of lysosomes by G4 ligands.

Centre de Recherche des Cordeliers INSERM UMRS 1138 Sorbonne Université Université Paris Cité Equipe labellisée par la Ligue contre le Cancer Institut universitaire de France Paris France

CNRS UMR9187 INSERM U1196 Université Paris Saclay Orsay France

Department of Biophysical Chemistry and Molecular Oncology Institute of Biophysics The Czech Academy of Sciences Brno Czech Republic

Department of Medicine 3 Klinikum Rechts der Isar Technical University of Munich Munich Germany

Institut du Cancer Paris CARPEM Department of Biology Hôpital Européen Georges Pompidou AP HP Paris France

Laboratoire d'Optique et Biosciences Ecole Polytechnique CNRS INSERM Institut Polytechnique de Paris 91128 Palaiseau France

Metabolomics and Cell Biology Platforms Institut Gustave Roussy Villejuif France

UFR SMBH Université Sorbonne Paris Nord Bobigny France

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