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Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair

The integration of a DNA copy of an HIV-1 RNA genome into the host genome, carried out by the viral enzyme integrase, results in the formation of single-stranded gaps in cellular DNA that must be repaired. Here, we have analyzed the involvement of the PI3K kinases, ATM, ATR, and DNA-PKcs, which are...

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Autores principales: Anisenko, Andrey, Nefedova, Anastasiia, Agapkina, Yulia, Gottikh, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917498/
https://www.ncbi.nlm.nih.gov/pubmed/36769109
http://dx.doi.org/10.3390/ijms24032797
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author Anisenko, Andrey
Nefedova, Anastasiia
Agapkina, Yulia
Gottikh, Marina
author_facet Anisenko, Andrey
Nefedova, Anastasiia
Agapkina, Yulia
Gottikh, Marina
author_sort Anisenko, Andrey
collection PubMed
description The integration of a DNA copy of an HIV-1 RNA genome into the host genome, carried out by the viral enzyme integrase, results in the formation of single-stranded gaps in cellular DNA that must be repaired. Here, we have analyzed the involvement of the PI3K kinases, ATM, ATR, and DNA-PKcs, which are important players in the DNA damage response (DDR) in HIV-1 post-integrational DNA repair (PIR). The participation of the DNA-PK complex in HIV-1 PIR has been previously shown, and the formation of a complex between the viral integrase and the DNA-PK subunit, Ku70, has been found to be crucial for efficient PIR. Now, we have shown that the inhibition of both DNA-PKcs and ATM, but not ATR, significantly reduces PIR efficiency. The activation of both kinases is a sequential process, where one kinase, being activated, activates the other, and it occurs simultaneously with the integration of viral DNA. This fact suggests that the activation of both kinases triggers PIR. Most interestingly, the activation of not only DNA-PKcs, but also ATM depends on the complex formation between integrase and Ku70. The elucidation of the interactions between viruses and DDR is important both for understanding the modulation of host cell functions by these pathogens and for developing new approaches to combat viral infections.
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spelling pubmed-99174982023-02-11 Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair Anisenko, Andrey Nefedova, Anastasiia Agapkina, Yulia Gottikh, Marina Int J Mol Sci Article The integration of a DNA copy of an HIV-1 RNA genome into the host genome, carried out by the viral enzyme integrase, results in the formation of single-stranded gaps in cellular DNA that must be repaired. Here, we have analyzed the involvement of the PI3K kinases, ATM, ATR, and DNA-PKcs, which are important players in the DNA damage response (DDR) in HIV-1 post-integrational DNA repair (PIR). The participation of the DNA-PK complex in HIV-1 PIR has been previously shown, and the formation of a complex between the viral integrase and the DNA-PK subunit, Ku70, has been found to be crucial for efficient PIR. Now, we have shown that the inhibition of both DNA-PKcs and ATM, but not ATR, significantly reduces PIR efficiency. The activation of both kinases is a sequential process, where one kinase, being activated, activates the other, and it occurs simultaneously with the integration of viral DNA. This fact suggests that the activation of both kinases triggers PIR. Most interestingly, the activation of not only DNA-PKcs, but also ATM depends on the complex formation between integrase and Ku70. The elucidation of the interactions between viruses and DDR is important both for understanding the modulation of host cell functions by these pathogens and for developing new approaches to combat viral infections. MDPI 2023-02-01 /pmc/articles/PMC9917498/ /pubmed/36769109 http://dx.doi.org/10.3390/ijms24032797 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Anisenko, Andrey
Nefedova, Anastasiia
Agapkina, Yulia
Gottikh, Marina
Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title_full Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title_fullStr Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title_full_unstemmed Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title_short Both ATM and DNA-PK Are the Main Regulators of HIV-1 Post-Integrational DNA Repair
title_sort both atm and dna-pk are the main regulators of hiv-1 post-integrational dna repair
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917498/
https://www.ncbi.nlm.nih.gov/pubmed/36769109
http://dx.doi.org/10.3390/ijms24032797
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