# Mechanisms of Circadian Clock Control of mRNA Translation

> **NIH NIH R35** · TEXAS A&M UNIVERSITY · 2024 · $750,857

## Abstract

Summary
 The circadian clock, critical to human health and drug metabolism, regulates rhythmic protein production
and thus cell function and metabolism. Many proteins whose levels show robust circadian rhythms are produced
from mRNAs that are not rhythmic. Using the model eukaryote Neurospora crassa, we found that up to half of
this circadian regulation of protein levels is through clock control of the activities of a conserved regulator of
translation initiation (eIF2α), and the protein composition of translating ribosomes. We also made the surprising
observation that the circadian clock controls the probability that ribosomes will read through the normal stop
codon to produce proteins with carboxy-terminal extensions and potentially new functions. In addition, we found
that the clock regulates the levels of tRNA synthetases that charge tRNAs with the appropriate amino acids for
translation, and thus are critical for accurate protein synthesis. Over the next 5 years, we will capitalize on these
findings to test the exciting hypothesis that the circadian clock controls daily changes in translation fidelity and
thus protein diversity beyond what is encoded for in the genome. We will determine if clock control of ribosome
composition is necessary, and which specific ribosomal proteins are required, for rhythmic stop codon
readthrough. In addition, we will test if circadian clock control of binding of the co-chaperone Zuotin to ribosomes
regulates daily rhythms in protein folding. We will determine the impact of circadian rhythms in methionyl-tRNA
synthetase (MetRS) levels, and rhythms in the activities of kinases that phosphorylate MetRS, on three different
MetRS regulatory pathways. These include translation initiation through charging of the initiator methionyl tRNA,
translation elongation through charging of elongator methionyl tRNA, and misincorporation of methionine during
protein synthesis through the mischarging of non-cognate tRNA. This work will significantly impact our
understanding of both how a cell is different at different times of the day, and how the proteome can be more
diverse than what one would predict from the genome sequence.

## Key facts

- **NIH application ID:** 10836997
- **Project number:** 5R35GM126966-07
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Deborah Bell-Pedersen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $750,857
- **Award type:** 5
- **Project period:** 2018-05-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836997

## Citation

> US National Institutes of Health, RePORTER application 10836997, Mechanisms of Circadian Clock Control of mRNA Translation (5R35GM126966-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10836997. Licensed CC0.

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