# Regulation of ribosome collisions during health, development and disease

> **NIH NIH R00** · VANDERBILT UNIVERSITY · 2024 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Obstacles on mRNAs cause eukaryotic ribosomes to stall. Severely stalled ribosomes collide with
the upstream, translating ribosomes and form a complex of two ribosomes, referred to as “disome”,
which is detected and removed by the Ribosome Quality Control (RQC) pathway. By establishing
Disome-seq technique, which reveals genome-wide distribution of ribosome collisions across the
transcriptome, we showed that RQC-targeted disomes frequently form on yeast mRNAs. We also found
that collisions in yeast trigger the Integrated Stress Response (ISR), which reduces translation while
inducing the expression of survival genes. Similarly, disomes activate ISR in humans to promote survival,
but its hyperactivation leads to cell death. This indicates that cellular health is determined by disome
homeostasis, which collectively refers to the disome distribution across transcripts, the overall disome
abundance and the downstream response evoked by RQC/ISR. The mechanisms by which RQC and
ISR detect disomes and affect collision dynamics, however, are poorly understood. The mutations of
RQC and ISR components as well as dysregulated ribosome stalling have been linked to
neurodevelopmental and neurodegenerative diseases. However, the contribution of disome homeostasis
to neuronal differentiation and function is unclear.
 The objective of this proposal is to determine the mechanisms of disome homeostasis, to
examine the role of disome regulation in neurons and to understand how its dysregulation leads to
diseases. I hypothesize that regulation of disome homeostasis is important for neurodevelopment and
neuronal health, and its dysregulation causes neuronal pathologies. In Aim 1, I will determine the
mechanism of disome recognition by RQC and ISR in healthy and stressed cells by using selective
Disome-seq and single-molecule fluorescence microscopy. In Aim 2, I will determine the distribution and
abundance of disomes, and the role of RQC/ISR factors during the differentiation of induced pluripotent
stem cells (iPSCs) into mature neurons by using fluorescence reporters, Disome-seq and neuronal
assays. In Aim 3, I will delineate the link between dysregulation of disome homeostasis and neuronal
diseases that were proposed to affect ribosome stalling by using Disome-seq, RNA-seq, RQC/ISR
reporters and phenotypic experiments in the cells with disease mutations. I will further test the translation
inhibitors as potential therapeutics to ameliorate the disease phenotypes. Overall, proposed work will
illuminate crucial insights into the regulation of ribosome collisions and their role in neuronal homeostasis.

## Key facts

- **NIH application ID:** 11031075
- **Project number:** 4R00GM144688-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Fatma Sezen Meydan Marks
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11031075

## Citation

> US National Institutes of Health, RePORTER application 11031075, Regulation of ribosome collisions during health, development and disease (4R00GM144688-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11031075. Licensed CC0.

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