{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:52:54Z","timestamp":1789087974463,"version":"build-2803163510"},"reference-count":117,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse (NIDA)","award":["R01DA041746"],"award-info":[{"award-number":["R01DA041746"]}]},{"name":"National Institute on Drug Abuse (NIDA)","award":["1R21MH126998-01A1"],"award-info":[{"award-number":["1R21MH126998-01A1"]}]},{"name":"National Institute on Mental Health (NIMH)","award":["R01DA041746"],"award-info":[{"award-number":["R01DA041746"]}]},{"name":"National Institute on Mental Health (NIMH)","award":["1R21MH126998-01A1"],"award-info":[{"award-number":["1R21MH126998-01A1"]}]},{"name":"National Institute of Health","award":["R01DA041746"],"award-info":[{"award-number":["R01DA041746"]}]},{"name":"National Institute of Health","award":["1R21MH126998-01A1"],"award-info":[{"award-number":["1R21MH126998-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages of HIV transcription, thereby promoting HIV replication. Additionally, our study demonstrates that the cocaine-induced DNA-PK promotes the hyper-phosphorylation of the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) at Ser5 and Ser2 sites, enhancing both the initiation and elongation phases, respectively, of HIV transcription. The cocaine-mediated enhancement of transcriptional initiation is supported by its activation of cyclin-dependent kinase 7 (CDK7). Additionally, the induction of transcriptional elongation is marked by higher LTR recruitment and the increased phosphorylation of CDK9, which indicates the stimulation of positive transcriptional elongation factor b (P-TEFb). We demonstrate for the first time that cocaine, through DNA-PK activation, promotes the specific phosphorylation of TRIM28 at serine 824 (p-TRIM28, S824). This modification converts TRIM28 from a transcriptional inhibitor to a transactivator for HIV transcription. Additionally, we observed that the phosphorylation of TRIM28 (p-TRIM28, S824) promotes the transition from the pausing phase to the elongation phase of HIV transcription, thereby facilitating the production of full-length HIV genomic transcripts. This finding corroborates the previously observed enhanced RNAP II CTD phosphorylation at Ser2, a marker of transcriptional elongation, following cocaine exposure. Accordingly, upon cocaine treatment, we observed the elevated recruitment of p-TRIM28-(S824) at the HIV LTR. Overall, our results unravel the intricate molecular mechanisms underlying cocaine-induced HIV transcription and gene expression. These findings hold promise for the development of highly targeted therapeutics aimed at mitigating the detrimental effects of cocaine in individuals living with HIV.<\/jats:p>","DOI":"10.3390\/cells13231950","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T05:21:32Z","timestamp":1732512092000},"page":"1950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cocaine-Induced DNA-Dependent Protein Kinase Relieves RNAP II Pausing by Promoting TRIM28 Phosphorylation and RNAP II Hyperphosphorylation to Enhance HIV Transcription"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9969-8642","authenticated-orcid":false,"given":"Adhikarimayum Lakhikumar","family":"Sharma","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenata","family":"Khumallambam","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-8051","authenticated-orcid":false,"given":"Mudit","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.2119\/molmed.2012.00194","article-title":"Human immunodeficiency virus (HIV) latency: The major hurdle in HIV eradication","volume":"18","author":"Tyagi","year":"2012","journal-title":"Mol. 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