# Mechanism for post-transcriptional gene regulation by Ribothrypsis

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $97,050

## Abstract

PROJECT SUMMARY/ ABSTRACT
Post-transcriptional regulation of gene expression is fundamental to normal cellular homeostasis. The current
model in the field of biology is that mRNAs exist primarily as ‘full-length’ molecules that are ‘protected’ from
decay by ribosomes during translation. The long-established understanding is that mRNA decay is initiated by
deadenylation followed by decapping and subsequent exonucleolytic decay from both ends. Co-translational
mRNA decay is known to occur mainly in defective mRNAs. Existing next-generation sequencing methods that
profile mRNA decay target either the 5’ or 3’ ends, thus missing information about the other end that could
illuminate new insights into mRNA decay. During my post-doctoral training, I developed several novel
transcriptome-wide sequencing methods that concurrently select both ends of mRNAs. I discovered a novel
mechanism of co-translational decay of canonical mRNAs that involves repeated endonucleolytic cleavage
events, mediated by translating ribosomes that we named “ribothrypsis”. Ribothrypsis is conserved between
humans and yeast. We identified the unexpected ribosome-phased mRNAs fragmentation and found that
deadenylation is not a prerequisite for mRNA decay. Our discovery of ribothrypsis revealed that co-translational
mRNA decay is more widespread than previously thought. The central hypothesis of this proposal is that
ribothrypsis is an evolutionarily conserved mechanism for modulating gene expression that can be triggered by
numerous factors to recruit an unknown endonuclease that we termed “ribothrypsin”. We propose here to
capitalize on our past discoveries and leverage cutting-edge novel RNA sequencing methods to achieve a
comprehensive understanding of the mechanistic underpinnings of ribothrypsis and its regulation. In this
proposal, we will investigate (i) the impact of cellular conditions that induce ribosome stalling on RNA decay
intermediates; (ii) the conservation of ribothrypsis in other eukaryotes; (iii) the identity of ribothrypsin; and (iv)
the role of RNA modifications in triggering ribothrypsis. These goals are mirrored by our long-term objective to
understand the mechanisms that underlie RNA decay dysregulation in human diseases. The molecular insights
gained in this proposal could also broaden our understanding of ribosome biology and RNA modifications.

## Key facts

- **NIH application ID:** 11100745
- **Project number:** 3R01GM149825-02S1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** FADIA Fayez IBRAHIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $97,050
- **Award type:** 3
- **Project period:** 2023-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100745

## Citation

> US National Institutes of Health, RePORTER application 11100745, Mechanism for post-transcriptional gene regulation by Ribothrypsis (3R01GM149825-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11100745. Licensed CC0.

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