# Structural biology of 7SK RNP and its interaction with HIV-1 Tat

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $479,352

## Abstract

PROJECT SUMMARY/ABSTRACT
The human 7SK RNP is a dynamic assembly of the long non-coding 7SK RNA and cellular proteins that
regulates the activity of positive transcription elongation factor b (P-TEFb). P-TEFb is an essential eukaryotic
transcription factor for mRNA transcription elongation, which regulates the transition from promoter proximal
paused RNA polymerase II (RNAPII) into productive elongation. P-TEFb is also an essential human cofactor
for HIV-1 Tat transactivation and therefore viral replication. The human 7SK core RNP comprises the 331 nt
RNAPIII-transcribed non-coding 7SK RNA, an unusual methyl capping enzyme called MePCE that methylates
the γ phosphate on the RNA 5' terminus, and the La related protein 7, Larp7, that associates with the terminal
hairpin and UUU-3'OH. In the active 7SK snRNP, Hexim and P-TEFb, a heterodimer of Cyclin T1 and the
kinase Cdk9, bind the 7SK core RNP; interaction of P-TEFb in this complex inactivates it by sequestering its
active site. Despite the central role of 7SK in transcription regulation of mRNA, other RNAPII RNAs, and HIV-1
transcription, relatively little is known at a structural or mechanistic level about how cellular proteins assemble
with 7SK RNA to form a functional 7SK RNP or how Tat interacts with it to ultimately release P-TEFb. We will
employ a combination of NMR spectroscopy, X-ray crystallography, and cryo electron microscopy along with
biochemical methods to investigate the structures and assembly of the 7SK core RNP (MePCE–7SK–Larp7)
and 7SK core RNP plus Hexim and P-TEFb (the `active' 7SK RNP) in order to achieve an atomic-level
understanding of this important host RNP for HIV-1 viral replication. These structural studies will lay the
groundwork for elucidating the molecular mechanisms of Tat-Hexim competition in the context of 7SK RNP.
We aim to dissect the potential intermediate steps (i.e. Tat-bound 7SK RNP) that lead to P-TEFb hijacking
from 7SK RNP into the HIV-1 viral super-elongation complex. The results of these experiments will provide
fundamental molecular insights into and a structural basis for drug targeting of this largely structurally
uncharacterized RNP that is essential for HIV-1 transcription and therefore escape from latency.

## Key facts

- **NIH application ID:** 10170271
- **Project number:** 5R01AI155170-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** JULI FEIGON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $479,352
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170271

## Citation

> US National Institutes of Health, RePORTER application 10170271, Structural biology of 7SK RNP and its interaction with HIV-1 Tat (5R01AI155170-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170271. Licensed CC0.

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