# Structural understanding of 7SK-snRNP mediated transcriptional regulation

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $484,772

## Abstract

Abstract
During transcription of many cellular and viral mRNAs, RNA Polymerase II is inhibited by
negative elongation factors and requires the positive elongation factor, pTEFb, to release this
stalled state. The binding of the 7SK small nuclear RNA to the HEXIM adapter protein as a part
of the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex normally keeps pTEFb
sequestered within the nucleus and this interaction must be overcome for productive
transcriptional elongation. The most well-studied example of the regulatory mechanisms that
underlie transcriptional elongation is the HIV Tat system. Briefly, in order to release the stalled
state of its transcript, HIV has evolved the viral Tat protein, which binds 7SK and displaces
HEXIM to hijack pTEFb. On the other hand, some cellular factors, like BRD4, achieve the same
outcome without displacing HEXIM. This proposal aims to gain a mechanistic understanding of
the structural state presented to all transcriptional regulators encountering an HEXIM-driven
inhibitory 7SK snRNP complex, and how capture of pTEFb is achieved by the specialized HIV
Tat transcriptional factor. The aims will be: (#1) to understand if the basic mechanisms are
maintained in HEXIM1 and 2 and if diverse positive transcriptional regulators capitalize on the
mechanism, (#2) to determine the structures of the individual RNA domains present in 7SK-
snRNA and (#3) to solve the structures of both HEXIM-bound and Tat-bound complexes.

## Key facts

- **NIH application ID:** 10922669
- **Project number:** 5R01GM144374-02
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Victoria Manuel D'Souza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,772
- **Award type:** 5
- **Project period:** 2023-09-06 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922669

## Citation

> US National Institutes of Health, RePORTER application 10922669, Structural understanding of 7SK-snRNP mediated transcriptional regulation (5R01GM144374-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10922669. Licensed CC0.

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