# Biology of RNA G-quadruplexes

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $375,900

## Abstract

Summary
 G-quadruplexes (G4s) are non-canonical secondary structures in nucleic acids that are formed by
guanine-rich sequences. G4 structural and functional studies have largely focused on DNA G4s, and the
number of biological functions assigned to these motifs has grown rapidly since the discovery of their
involvement in telomere biology. RNA G4s (RG4s) are less studied, but interest is increasing due to their
association with multiple processes. A comprehensive understanding of how RNA G4s contribute to cell
physiology and pathophysiology is the long-term research goal of the applicant.
 Multiple reports clearly demonstrate that G4s are enriched in mRNA 5’- and 3’-untranslated regulatory
regions. There is an increasing evidence that RG4s control gene expression at transcriptional and post-
transcriptional levels, although such data is largely based on in vitro studies. Testing the biological significance
of RG4s requires proving that RG4s exist in vivo. Intriguingly, RG4s appear predominantly unfolded in
eukaryotic cells, whereas they are readily folded in vitro, suggesting that in cells RG4s are constitutively
recognized and actively unfolded. We hypothesize that RG4 folding-unfolding regulates mRNA homeostasis.
This hypothesis is based on our analysis of human transcriptome that identifies RG4s as stress-responsive
RNA elements. We will test this hypothesis with three specific aims. In AIM1, we will determine and
characterize the fraction of the human transcriptome that contains putative stress-responsive RG4s in living
cells. In AIM2, we will identify bona fide RG4-binding proteins using a novel approach based on
proteomic/biochemical analysis of interactions between the 7-deazaguanine RNA derivatives and proposed
binding factors. In AIM 3, we will use functional assays to determine the biological significance of RG4s in
mRNA stability, localization and translation. We will use biophysical and biochemical methods to validate
selected RG4 candidates. This work will elucidate how RG4-mediated functions contribute to cellular mRNA
homeostasis, and will identify physiologically significant RG4-binding partners, which in turn may reveal
molecular targets and pathways with therapeutic potential.
 The understanding of cellular functions of RG4 motifs is particularly relevant to the biology of cancer
and neurodegeneration. RNA regions containing RG4s significantly overlap with regions containing disease-
associated mutations. The proposed studies may elucidate molecular events underlying normal and
pathological aspects of cell physiology, and identify events contributing to the tumorigenic or
neurodegenerative changes.

## Key facts

- **NIH application ID:** 10093075
- **Project number:** 5R01GM126150-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Pavel Ivanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,900
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093075

## Citation

> US National Institutes of Health, RePORTER application 10093075, Biology of RNA G-quadruplexes (5R01GM126150-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093075. Licensed CC0.

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