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

Retrovirology

Review

Carmelo Di Primo¹  Jean-Louis Mergny²  Mingpan Cheng³  Violaine Saint-André⁴  Melissa Rodrigues⁵  Elouan Perrot⁵  Danielle Gadelle⁶  Stéphane Emiliani⁷  Clarisse Berlioz-Torrent⁷  Emmanuel Segeral⁷  María José Lista⁸  Marc Lavigne⁹  Elenia Toccafondi^1,10  Anne-Caroline Jousset^1,10 

[1] CNRS UMR 5320, INSERM U1212, ARNA, Univ. Bordeaux, IECB, 33000, Bordeaux, France;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;CNRS UMR 5320, INSERM U1212, ARNA, Univ. Bordeaux, IECB, 33000, Bordeaux, France;School of Engineering, China Pharmaceutical University, 211198, Nanjing, China;Institut Pasteur, Bioinformatics and Biostatistics Hub, Université Paris Cité, 75015, Paris, France;Institut Pasteur, Departement of Virology, Université Paris Cité, 75015, Paris, France;Institut de Biologie Integrative de la Cellule, CNRS, Université Paris-Saclay, 91198, Gif Sur Yvette, Cedex, France;Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France;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;Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014, Paris, France;Institut Pasteur, Departement of Virology, Université Paris Cité, 75015, Paris, France;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;

关键词: Guanine quadruplex;    HIV-1 LTR promoter;    HIV-1 transcription;    HIV-1 latency;    DNA topoisomerases;    Transcriptional regulation;    Host-virus interaction;   

DOI  :  10.1186/s12977-023-00625-8

 received in 2023-02-23, accepted in 2023-05-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundOnce 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.ResultsIn 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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