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- W2947048166 abstract "Author(s): Faust, Tyler Bischoff | Advisor(s): Frankel, Alan D | Abstract: HIV-1 gene expression has provided an excellent model of transcription elongation control. Transcription complexes that assemble at the HIV-1 promoter efficiently initiate transcription but generate paused RNA polymerase II downstream from the start site. The virally encoded Tat protein hijacks P-TEFb to phosphorylate and activate this paused polymerase. Tat binds additional host proteins, but it is unclear if and how they regulate RNAP II elongation. Further, Tat is a particularly small, natively unfolded protein, so it is puzzling how this viral transcription factor is able to bind and redirect the activity of multiple, large host complexes. In this thesis we address these questions by first identifying all Tat amino acids that are essential for its transcriptional activity. The analysis of HIV-1 sequences from infected patients, the activities of an entire set of Tat alanine point mutants, and the replication efficiencies of a randomly mutagenized library of Tat alleles cloned into the virus reveal that Tat and Rev segregate their functional residues in their overlapping coding sequence. Next, a candidate RNAi screen of previously identified novel Tat host interactors reveals that multiple proteins involved in ubiquitin conjugation are essential for Tat activity. Using in vivo purifications and in vitro reconstitution, we show that PJA2, a RING-H2 E3 ubiquitin ligase, directly ubiquitinates Tat. Extensive mutagenesis of Tat and ubiquitin expression constructs reveals both that multiple lysines in Tat can serve as ubiquitin acceptor sites and that multiple lysines in ubiquitin can be used to generate polyubiquitin chains. This immense plasticity of ubiquitin signaling through Tat is likely a way for the virus to encode a transcriptional activity that is robust to a high mutation rate. Using a similar approach, we then demonstrate that Tat hijacks the UBE2O ligase to robustly ubiquitinate specific proteins in the 7SK snRNP. Surprisingly, this ubiquitination occurs in the cytoplasm and functions to remodel the snRNP complex. Remarkably, Tat targets the cytoplasmic 7SK snRNP, releasing P-TEFb from its inhibitor, resulting in nuclear import of the free kinase to activate transcription. This re-localization provides a unique paradigm for P-TEFb control." @default.
- W2947048166 created "2019-06-07" @default.
- W2947048166 creator A5036058020 @default.
- W2947048166 date "2016-01-01" @default.
- W2947048166 modified "2023-09-27" @default.
- W2947048166 title "Ubiquitin signaling regulates multiple steps in Tat-dependent HIV-1 transcription" @default.
- W2947048166 hasPublicationYear "2016" @default.
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