DNA topoisomerase 1 represses HIV-1 promoter activity through its interaction with a guanine quadruplex present in the LTR sequence.

Autor: Lista MJ; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France.; Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK., Jousset AC; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France.; Université de Strasbourg, CNRS UPR 9002, Architecture et réactivité de l'ARN, 67000, Strasbourg, France., Cheng M; CNRS UMR 5320, INSERM U1212, ARNA, Univ. Bordeaux, IECB, 33000, Bordeaux, France.; School of Engineering, China Pharmaceutical University, Nanjing, 211198, China., Saint-André V; Institut Pasteur, Bioinformatics and Biostatistics Hub, Université Paris Cité, 75015, Paris, France., Perrot E; Institut Pasteur, Departement of Virology, Université Paris Cité, 75015, Paris, France., Rodrigues M; Institut Pasteur, Departement of Virology, Université Paris Cité, 75015, Paris, France., Di Primo C; CNRS UMR 5320, INSERM U1212, ARNA, Univ. Bordeaux, IECB, 33000, Bordeaux, France., Gadelle D; Institut de Biologie Integrative de la Cellule, CNRS, Université Paris-Saclay, 91198, Gif Sur Yvette, Cedex, France., Toccafondi E; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France.; Université de Strasbourg, CNRS UPR 9002, Architecture et réactivité de l'ARN, 67000, Strasbourg, France., Segeral E; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France., Berlioz-Torrent C; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France., Emiliani S; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France., Mergny JL; CNRS UMR 5320, INSERM U1212, ARNA, Univ. Bordeaux, IECB, 33000, Bordeaux, France.; Laboratoire d'Optique et Biosciences, Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, 91120, Palaiseau, France., Lavigne M; Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France. marc.lavigne@pasteur.fr.; Institut Pasteur, Departement of Virology, Université Paris Cité, 75015, Paris, France. marc.lavigne@pasteur.fr.
Jazyk: angličtina
Zdroj: Retrovirology [Retrovirology] 2023 May 30; Vol. 20 (1), pp. 10. Date of Electronic Publication: 2023 May 30.
DOI: 10.1186/s12977-023-00625-8
Abstrakt: Background: Once integrated in the genome of infected cells, HIV-1 provirus is transcribed by the cellular transcription machinery. This process is regulated by both viral and cellular factors, which are necessary for an efficient viral replication as well as for the setting up of viral latency, leading to a repressed transcription of the integrated provirus.
Results: In this study, we examined the role of two parameters in HIV-1 LTR promoter activity. We identified DNA topoisomerase1 (TOP1) to be a potent repressor of this promoter and linked this repression to its catalytic domain. Additionally, we confirmed the folding of a Guanine quadruplex (G4) structure in the HIV-1 promoter and its repressive effect. We demonstrated a direct interaction between TOP1 and this G4 structure, providing evidence of a functional relationship between the two repressive elements. Mutations abolishing G4 folding affected TOP1/G4 interaction and hindered G4-dependent inhibition of TOP1 catalytic activity in vitro. As a result, HIV-1 promoter activity was reactivated in a native chromatin environment. Lastly, we noticed an enrichment of predicted G4 sequences in the promoter of TOP1-repressed cellular genes.
Conclusions: Our results demonstrate the formation of a TOP1/G4 complex on the HIV-1 LTR promoter and its repressive effect on the promoter activity. They reveal the existence of a new mechanism of TOP1/G4-dependent transcriptional repression conserved between viral and human genes. This mechanism contrasts with the known property of TOP1 as global transcriptional activator and offers new perspectives for anti-cancer and anti-viral strategies.
(© 2023. The Author(s).)
Databáze: MEDLINE
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