# Regulation of transcriptional activation by protein disorder

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $318,706

## Abstract

Regulation of transcriptional activation by protein disorder
PIs: Daughdrill/Chen
Abstract
The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription
to regulate cell survival and proliferation. It is mutated in at least 50% of solid tumors and some of these
mutants are oncogenic and activate the transcription of genes that promote cell survival and metastasis.
Despite decades of research on p53, there are currently no FDA approved drugs in the clinic that directly
target wt or mutant p53. This is, in part, because 50% of p53 is disordered and we have an incomplete
understanding of what these regions look like and how they function. We have recently shown that the
disordered N-terminal acidic transactivation domain of p53 (NT) dynamically interacts with the DNA
binding domain (DBD) with residues that contact DNA. This interaction inhibits DNA binding but
increases binding specificity using a combination of nucleic acid mimicry and electrostatic shielding that
enhances recognition of promoter binding sites in vivo. We propose to: (1) Determine the specific effects
of nucleic acid mimicry and electrostatic shielding on DNA binding specificity, and how tethering controls
the intramolecular interaction between NT and DBD. (2) Investigate how p53 NT phosphorylation
regulates DNA binding affinity and specificity to create adaptable switching of transcriptional activation.
(3) Determine how MdmX interferes with p53 DNA binding when it forms a heterodimer with p53.
Successful completion of these experiments will lead to a better understanding of how p53 governs cell
fate after DNA damage by regulating the binding specificity to pro-survival versus pro-apoptotic target
genes. A deeper understanding of the structural and functional properties of the weak dynamic
interactions within p53 and between p53 and MdmX is necessary for the successful development of
small molecules to target these interactions for cancer therapy.

## Key facts

- **NIH application ID:** 10247077
- **Project number:** 5R01GM115556-06
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** JIANDONG CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,706
- **Award type:** 5
- **Project period:** 2016-06-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247077

## Citation

> US National Institutes of Health, RePORTER application 10247077, Regulation of transcriptional activation by protein disorder (5R01GM115556-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247077. Licensed CC0.

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