# Mechanisms of Circadian Clock Control of mRNA Translation

> **NIH NIH R35** · TEXAS A&M UNIVERSITY · 2020 · $707,931

## Abstract

Project Summary
 The circadian clock is an evolutionarily conserved time-keeping mechanism that, through the regulation of
rhythmic gene expression, coordinates the physiology of an organism with daily environmental cycles.
Because nearly all aspects of human physiology and behavior are linked to the clock, clock dysfunction is
associated with a wide range of diseases, including sleep disorders, cardiovascular disease, metabolic
syndrome, and cancer. In addition, the clock controls the efficacy and toxicity of many drugs. Therefore,
identifying what genes and proteins are regulated by the clock, and determining the mechanisms for this
regulation, are key to understanding clock-associated diseases and rhythmic drug metabolism.
 While the primary focus of research on circadian control of gene expression has been at the transcriptional
level, recent evidence supports a role for the clock in regulating posttranscriptional mechanisms. How the clock
regulates mRNA translation is poorly understood. We found that the Neurospora crassa circadian clock
controls the phosphorylation of two highly conserved central regulators of mRNA translation, eukaryotic
elongation factor 2 (eEF2), and eukaryotic initiation factor 2α (eIF2α). Using high throughput RNA-seq and
ribosome profiling in wild type cells, and cells that are defective in rhythmic activity of the translation factors, we
found that clock regulation of translation factor activity affects translation of specific mRNAs, rather than acting
globally to regulate translation of all mRNAs. During the next 5 years, we will leverage our expertise and tools
to determine the mechanisms for this specificity. In an exciting breakthrough, we found that the clock controls
the composition of cytoplasmic ribosomes, whereby certain ribosomal proteins cycle in abundance in
ribosomes. These data challenge the paradigm that all cytoplasmic ribosomes are the same, and instead
suggest the existence of heterologous ribosomes with distinct functions. We will capitalize on these findings to
test the hypothesis that changes in ribosome protein composition, modification, and/or interactions with
accessory proteins occur temporally under control of the clock. Elucidating the clock-regulated ribosome
modification mechanism may also lead to insights into unexpected ways that signals other than the clock might
postranscriptionally regulate protein expression.

## Key facts

- **NIH application ID:** 9923685
- **Project number:** 5R35GM126966-03
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Deborah Bell-Pedersen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $707,931
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923685

## Citation

> US National Institutes of Health, RePORTER application 9923685, Mechanisms of Circadian Clock Control of mRNA Translation (5R35GM126966-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9923685. Licensed CC0.

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