# Understanding genome-wide and single-molecule dynamics of colliding ribosomes during health and disease

> **NIH NIH FI2** · U.S. NATIONAL INST DIABETES/DIGST/KIDNEY · 2020 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
 Eukaryotic ribosomes translating defective mRNAs, such as those that are damaged,
“stall” and become unavailable for new rounds of translation. The ribosome-associated quality
control (RQC) system detects the stalled complex formed by two collided ribosomes (“disome”)
and degrades the defective mRNAs to prevent aberrant translation. Since this pathway leads to
irreversible mRNA decay, it is critical for the RQC machinery to differentiate functional ribosome
pausing events, from aberrant ribosome stalling cases that need to be resolved. However,
previous RQC studies used artificial mRNA substrates that induce extreme cases of ribosome
stalling. Therefore, it is unknown how frequently and where disomes form on regular transcripts.
It is also unclear if RQC recognizes all disomes and what the cellular consequences of recognition
are. Interestingly, impaired ribosome collisions have been linked to a neurodevelopmental
disorder, Fragile-X syndrome (FXS), which is the most common form of inherited intellectual
disability. Nevertheless, the pathological dynamics of ribosome collisions during FXS as well as
the interplay between collisions and RQC pathway during neurodevelopment have been poorly
studied. There is a critical need, therefore, to determine the dynamics of ribosome collisions in
healthy cells and to understand how their dysregulation leads to FXS.
 The objective of this proposal is to determine the role of ribosome collisions during
neurodevelopment. My hypothesis is that under physiological conditions, RQC-targeted disomes
form on regular transcripts and they maintain neuronal homeostasis by regulating protein
expression. I further postulate that dysregulation of disome formation leads to cellular stress and
causes disease phenotypes. To test this idea, in aim 1, I will determine the genome-wide
distribution of disomes in human cells using the Disome-seq technique that we recently
established in our lab. To visualize the dynamics of RQC upon ribosome collision, in aim 2, I will
monitor real-time regulation of RQC using cutting-edge dual-color single molecule imaging in
human cells. To understand the functional role of ribosome collisions, in aim 3, I will characterize
the link between dysregulated ribosome stalling in an FXS model of neuronal differentiation. I will
further study the action of translation inhibitors for their potential of restoring the collisions in
neurons. Overall, the proposed studies aim to determine the prevalence of ribosome collisions in
the cell and how dysregulation of these collisions can cause neurodevelopmental defects.

## Key facts

- **NIH application ID:** 10026314
- **Project number:** 1FI2GM137845-01
- **Recipient organization:** U.S. NATIONAL INST DIABETES/DIGST/KIDNEY
- **Principal Investigator:** Fatma Sezen Meydan Marks
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026314

## Citation

> US National Institutes of Health, RePORTER application 10026314, Understanding genome-wide and single-molecule dynamics of colliding ribosomes during health and disease (1FI2GM137845-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026314. Licensed CC0.

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