# Tat-Host Transcription Complexes

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $381,754

## Abstract

Tat is a small HIV regulatory protein essential for viral replication whose well-known function is to enhance
transcription elongation from the viral promoter. Tat recruits the host elongation factor P-TEFb to TAR RNA to
phosphorylate the CTD of RNAP II. The activity of the Cdk9 kinase of P-TEFb is inhibited by the 7SK snRNP,
and we previously found that the inhibited complex is recruited to the HIV promoter during transcription
initiation and is ejected when TAR is synthesized thereby activating the kinase. Another set of host factors, the
super-elongation complex (SEC), operates later to further enhance Tat-mediated elongation. There has been
substantial recent progress on structural studies of Tat and its complexes, most notably Tat bound to P-TEFb
and components of the SEC. It is clear that Tat is a largely disordered protein that requires the P-TEFb
template for its folding, primarily through interactions with the cyclin T1 subunit. Despite this progress, the
transcription process is quite complex and dynamic and many other host factors come into play. Based on our
previous HARC proteomic studies, we have recently identified several new Tat cofactors important for its
function. One factor, PJA2, directly ubiqutinates lysines on Tat in a non-degradative manner to stimulate its
activity. Another set of three factors – ZFP91, UBE2O, and NAP1L4 – forms a cytoplasmic complex (ZUN) that
enhances Tat activity via ubiquitination of HEXIM1, a subunit of the 7SK snRNP. This non-degradative
modification, carried out by the UBE2O ligase, helps disassemble the inhibitory 7SK complex and releases PTEFb
to relocalize from the cytoplasm to the nucleus. Based on these novel findings, we will further our
structural studies of Tat and host complexes by: 1) examining ubiquitination of Tat by PJA2 and determining
structures of relevant complexes; 2) determining structures of Tat with novel 7SK snRNP complexes; and 3)
examining connections between 7SK snRNP complexes and the SEC. The discovery of the PJA2 and ZUN
complexes illustrates another way in which HIV has hijacked the host ubiquitination machinery to enhance its
replication. Advancing structural knowledge of these new Tat transcription complexes will illuminate their
mechanisms of action not only for the virus but also for host cell transcription.

## Key facts

- **NIH application ID:** 10229573
- **Project number:** 5P50AI150476-15
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ALAN D FRANKEL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,754
- **Award type:** 5
- **Project period:** 2007-08-27 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229573

## Citation

> US National Institutes of Health, RePORTER application 10229573, Tat-Host Transcription Complexes (5P50AI150476-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229573. Licensed CC0.

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