# Dynamic interplay of eukaryotic translation and mRNA decay

> **NIH NIH R00** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $249,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Translation of eukaryotic mRNAs is highly regulated, and mutations that prematurely halt translation cause 11%
of all heritable human diseases. Yet, it is unknown how ribosomes rapidly and accurately identify stop codons to
halt protein synthesis and release the nascent polypeptide. It is also unclear how ribosomes trapped on an
aberrant mRNA, such as those devoid of a stop codon, are liberated by decay machinery. An understanding of
these fundamental processes could facilitate the discovery of novel therapeutics for diseases such as Cystic
Fibrosis, Duchenne Muscular Dystrophy, and hereditary cancer syndromes. My central hypothesis is that the
slow rate at which aberrant mRNAs are translated by ribosomes is exploited by slowly-acting decay factors to
specifically degrade aberrant mRNAs and leave normal ones untouched. Examination of this hypothesis will
require real-time tracking of ribosomes translating normal or aberrant mRNAs, capturing intricacies of pathway
dynamics that are critical for regulation. As a postdoc in Joseph Puglisi’s lab at Stanford, I established single-
molecule assays to directly track individual eukaryotic ribosomes throughout termination using an in vitro-
reconstituted system. Co-mentored by Rachel Green, an expert in eukaryotic translation and mRNA decay, I will
extend these assays to monitor other key events in termination, recycling, and mRNA decay. I will further assess
the architecture of unique sub-states in translation and mRNA decay using cryo-EM. I propose the following
specific aims: (I) Decipher the mechanisms that ensure fidelity in eukaryotic termination; (II) Define the dynamics
that liberate ribosomes from normal and aberrant mRNAs; (III) Determine how termination, recycling, and mRNA
decay are regulated in humans. Together, the proposed aims will reveal how eukaryotic cells distinguish between
normal and aberrant mRNAs. Supported by my mentoring team, I will obtain expertise in cryo-EM, and the
additional training necessary to expand beyond my initial studies of translational control into related mRNA decay
mechanisms in yeast and humans. I will also become conversant in the language of genome-wide techniques
such as CRISPR screening and ribosome profiling. The proposed research and training activities will provide me
with the skills needed to establish an independent research program focused on the dynamic interplay of
eukaryotic translation and mRNA decay, and reveal fundamental facets of gene expression with relevance to
human health to be built upon in a future R01.

## Key facts

- **NIH application ID:** 10899622
- **Project number:** 5R00GM140209-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Michael R Lawson
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899622

## Citation

> US National Institutes of Health, RePORTER application 10899622, Dynamic interplay of eukaryotic translation and mRNA decay (5R00GM140209-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899622. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*