# INVESTIGATING THE CHAPERONE ACTIVITY OF NUCLEIC ACIDS

> **NIH NIH R00** · UNIVERSITY OF DENVER (COLORADO SEMINARY) · 2020 · $248,695

## Abstract

PROJECT SUMMARY
This project aims to understand how nucleic acids prevent protein aggregation and aid protein folding. Protein
misfolding and aggregation lead to many debilitating diseases, including Alzheimer's disease, Parkinson's
disease, and amyotrophic lateral sclerosis (ALS). In addition to many other roles in the cell, we recently
discovered that nucleic acids are powerful molecular chaperones. Chaperones are responsible for maintaining
proteome stability by preventing toxic protein aggregation and enabling protein folding. Given the
preponderance of nucleic acids in the cell, their role in stress granules, and their potent chaperone activity, it is
highly likely that they play a major role in protein homeostasis. At the current stage of investigation, we have
virtually no knowledge of how nucleic acids prevent protein aggregation, how they interact with other
chaperones, or what role they play in protein folding. This project will elucidate how nucleic acids work as
molecular chaperones, a previously unrecognized property of these important molecules.
 The work described in the K99 phase of this grant will provide me with the necessary skills to successfully
complete the R00 phase as an independent scientist and will lay the foundation for the R00 phase research. In
the K99 phase, I will learn new in vitro and in vivo techniques for characterizing chaperone function geared
towards nucleic acid chaperones. Using these techniques, I will examine the sequence specificity of nucleic
acid chaperones using a genetic screen (Aim 1A). I will then generate the foundation for the first model of how
nucleic acids prevent aggregation and participate in protein folding by studying how these sequences aid in
protein folding and interact with other chaperones (Aim 1B). I will also develop structural biology methods using
both NMR spectroscopy and X-ray crystallography to analyze complexes of chaperone-active nucleotide
chains and partially folded protein substrates (Aim 2).
 In the R00 phase of this project, I will continue to expand our studies of nucleic acid chaperone function to
include the larger structural vocabulary of RNA (Aim 1). I will also apply the structural biology techniques
developed in the K99 phase toward understanding the relationship between nucleic acid chaperone structure
and function, and elucidating how nucleic acid chaperones affect the folding of protein substrates (Aim 2).
Together, these data will allow us to construct a comprehensive model describing the chaperone function of
RNA and DNA. In the future, this model may form the basis for designing nucleic acid-based therapeutics for
currently untreatable protein misfolding diseases.

## Key facts

- **NIH application ID:** 9841404
- **Project number:** 5R00GM120388-04
- **Recipient organization:** UNIVERSITY OF DENVER (COLORADO SEMINARY)
- **Principal Investigator:** Scott Andrew Horowitz
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,695
- **Award type:** 5
- **Project period:** 2016-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841404

## Citation

> US National Institutes of Health, RePORTER application 9841404, INVESTIGATING THE CHAPERONE ACTIVITY OF NUCLEIC ACIDS (5R00GM120388-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9841404. Licensed CC0.

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