Cocaine-induced DNA-PK relieves RNAP II pausing by promoting TRIM28 phosphorylation.

Cocaine upregulates both the expression and activity of DNA-PK.Cocaine augments the phosphorylation of DNA-PK selectively at S2056, a post-translational modification that marks functionally active form of DNA-PK.Cocaine enhances the nuclear translocation of DNA-PK.The DNA-PK inhibition severely impairs HIV transcription, replication, and latency reactivation.Cocaine facilitates the initiation and elongation phases of HIV by enhancing RNAPII CTD phosphorylation at Ser5 and Ser2, respectively, by stimulating DNA-PK.Cocaine also supports initiation and elongation phases of HIV transcription by stimulating CDK7 (the kinase of TFIIH) and CDK9 (the kinase subunit of P-TEFb), respectively.Cocaine-mediated activation of DNA-PK relieves RNAP II pausing by reversing the inhibitory effect of pausing factor TRIM28 and converting it into a transactivator by catalyzing its phosphorylation at S824 site.Thus, cocaine, by activating DNA-PK, facilitates the multiple phases of HIV transcription, namely, initiation, RNAP II pause-release, and elongation.