DNA dependent protein kinase (DNA-PK) enhances HIV transcription by promoting RNA polymerase II activity and recruitment of transcription machinery at HIV LTR
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Sonia Zicari1,2,3,*, Adhikarimayum Lakhikumar Sharma1,*, Geetaram Sahu4,*, Larisa Dubrovsky5, Lin Sun4, Han Yue4, Tejaswi Jada4, Alex Ochem6, Gary Simon4, Michael Bukrinsky5 and Mudit Tyagi1,4,5
1 Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
2 Section of Intercellular Interactions, Eunice-Kennedy National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
3 Department of Pediatric Medicine, The Bambino Gesù Children's Hospital, Rome, Italy
4 Division of Infectious Diseases, Department of Medicine, George Washington University, Washington DC 20037, USA
5 Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC 20037, USA
6 International Centre for Genetic Engineering and Biotechnology (ICGEB), Wernher and Beit Building (South), Observatory 7925, Cape Town, South Africa
* These authors contributed equally to this work
|Mudit Tyagi,||email:||[email protected]|
Keywords: HIV; DNA-PK; transcription; replication; DNA-PK inhibitors
Received: October 07, 2017 Accepted: January 29, 2020 Published: February 18, 2020
Despite reductions in mortality from the use of highly active antiretroviral therapy (HAART), the presence of latent or transcriptionally silent proviruses prevents HIV cure/eradication. We have previously reported that DNA-dependent protein kinase (DNA-PK) facilitates HIV transcription by interacting with the RNA polymerase II (RNAP II) complex recruited at HIV LTR. In this study, using different cell lines and peripheral blood mononuclear cells (PBMCs) of HIV-infected patients, we found that DNA-PK stimulates HIV transcription at several stages, including initiation, pause-release and elongation. We are reporting for the first time that DNA-PK increases phosphorylation of RNAP II C-terminal domain (CTD) at serine 5 (Ser5) and serine 2 (Ser2) by directly catalyzing phosphorylation and by augmenting the recruitment of the positive transcription elongation factor (P-TEFb) at HIV LTR. Our findings suggest that DNA-PK expedites the establishment of euchromatin structure at HIV LTR. DNA-PK inhibition/knockdown leads to the severe impairment of HIV replication and reactivation of latent HIV provirus. DNA-PK promotes the recruitment of Tripartite motif-containing 28 (TRIM28) at LTR and assists the release of paused RNAP II through TRIM28 phosphorylation. These results provide the mechanisms through which DNA-PK controls the HIV gene expression and, likely, can be extended to cellular gene expression, including during cell malignancy, where the role of DNA-PK has been well-established.
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