# The Nucleolar Detention Center: A Hub of Long Noncoding RNA that Imprison Proteins during Stress

> **NIH NIH R35** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $383,750

## Abstract

Project Summary
The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and
pathological settings, including development, cancer and neurological disorders. Our group reported the
identification of stress-induced low complexity dinucleotide repeat noncoding RNA derived from stimuli-specific
loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically
dismissed as “junk” DNA. We showed that low complexity rIGSRNA initiate physiological amyloidogenic
programs that convert nucleoli into Amyloid-bodies: reversible fibrous membrane-less organelles composed of
immobilized proteins with amyloid-like features. While many membrane-less compartments have been described
as liquid-like (e.g., stress granules, P-bodies, germ cell granules), the discovery of Amyloid-bodies provided
evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state.
This rather unusual post-translational regulatory pathway enables the rapid and reversible storage of an array of
endogenous proteins in Amyloid-bodies to suppress metabolism in cells responding to severe environmental
insults. We propose to convert our NIGMS R01 grant funded in 2015 and renewed in 2018 to a MIRA under the
unifying theme “Function of low complexity rIGSRNA during stress”. Our research program includes in-depth
studies to understand (i) the mechanisms by which rIGSRNA activate physiological amyloidogenesis to construct
Amyloid-bodies and (ii) the function of rIGSRNA and Amyloid-bodies during stress. Studies outlined in this
proposal will involve isolated Amyloid-bodies, multi-color single molecule imaging of active translation sites
during stress, protein dynamics, long read sequencing of untemplated RNA, rRNA biology, and in vitro fibrillation
assays to understand the cellular and biochemical functions of low complexity RNA in cells engaging in anaerobic
metabolism, amongst other conditions. This NIGMS-funded research has enabled our laboratory to make
conceptual advances in our understanding of simple dinucleotide low complexity repeats in the genome. First,
the discovery that rIGRSNA construct Amyloid-bodies provided evidence that cells can activate physiological
liquid-to-solid phase transitions to assemble condensates with amyloid-like properties. These characteristics
distinguish Amyloid-bodies from the multitude of liquid condensates that populate mammalian cells, which
typically do not display amyloidogenic features. Our proposed work will not only shed light on adaptive
mechanisms to stressors but also provide alternative insights for the study of pathological amyloidogenesis
involved in an array of human neurological disorders. Second, the finding that low complexity RNA sequences
are functional determinants of rIGSRNA may stimulate research on the physiological role of long dinucleotide
intergenic repeats observed across the genome, but genera...

## Key facts

- **NIH application ID:** 10622035
- **Project number:** 1R35GM149221-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Stephen Lee
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $383,750
- **Award type:** 1
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10622035

## Citation

> US National Institutes of Health, RePORTER application 10622035, The Nucleolar Detention Center: A Hub of Long Noncoding RNA that Imprison Proteins during Stress (1R35GM149221-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10622035. Licensed CC0.

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