# Molecular mechanisms of mammalian circadian clock function

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $582,634

## Abstract

Abstract
Circadian clocks throughout the body drive rhythmic expression of thousands of genes, resulting in
rhythms in biochemistry, physiology and behavior. Disruption of circadian clocks through genetics or
environmental perturbations such as jet lag or shift-work, can have profound negative consequences
and has been linked to obesity, diabetes, cancer, cardiovascular disease and mental illness. Our
work is focused generally on understanding the detailed molecular mechanisms of the mammalian
circadian clock machinery and the mechanisms by which these clocks control rhythmic gene
expression. According to the current model, the core part of this clock mechanism is a negative
feedback loop whereby the transcription factor heterodimer CLOCK/BMAL1 drives transcription of the
“clock” proteins PERIOD (PER) 1, PER 2, CRYPTOCHROME (CRY) 1 and CRY 2 which interact with
each other to repress the activity of CLOCK/BMAL1, and thus their own synthesis. We have solved
crystal structures for the CLOCK/BMAL1 and CRY2/PER2 complexes and these data have allowed
the identification of evolutionarily conserved functional domains throughout the proteins and revealed
additional insights into the mechanisms by which these proteins operate and set the circadian period.
Over the next five years, we will expand on this information to determine the atomic details of how
this clock keeps time. The roles of these core circadian clock transcription factors in driving rhythmic
transcription is well-documented, but recent data have demonstrated that post-transcriptional control,
although much less well understood, is also critical for normal rhythmic protein expression profiles.
One type of post-transcriptional control is regulation of mRNA poly(A) tail length, which impacts the
stability and translational regulation of mRNA. We have identified hundreds of mouse liver mRNAs
that exhibit robust circadian rhythms in the length of their poly(A) tails. In many of these cases, the
rhythmic tail lengths are the result of rhythmic cytoplasmic polyadenylation and deadenylation
rhythms and many components of the cytoplasmic polyadenylation and deadenylation machinery are
themselves under circadian control. Furthermore, the rhythmic poly(A) tails are closely correlated
with the rhythmic protein expression. Therefore, the circadian clock regulates dynamic
polyadenylation status of many mRNAs that can drive rhythmic protein expression independent of the
steady-state levels of the message. Nocturnin is a robustly rhythmic protein that removes poly(A) tails
from mRNAs. We have shown that loss of this gene in mice causes resistance to diet-induced
obesity and altered rhythms in cholesterol and triglyceride metabolism, implicating it as an important
circadian post-transcriptional mediator. Over the next five years, we will focus on identifying the
mRNA substrates of Nocturnin both in the cytosol and in the mitochondria.

## Key facts

- **NIH application ID:** 10225593
- **Project number:** 5R35GM127122-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla B. Green
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $582,634
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225593

## Citation

> US National Institutes of Health, RePORTER application 10225593, Molecular mechanisms of mammalian circadian clock function (5R35GM127122-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225593. Licensed CC0.

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