# Roles of protein degradation in the circadian clock

> **NIH NIH R35** · MOREHOUSE SCHOOL OF MEDICINE · 2021 · $245,775

## Abstract

Project Summary/Abstract
 Circadian clocks influence nearly all aspects of mammalian life, aligning our internal
physiological process to optimal times of day. Understanding the molecular circuitry keeping
circadian time provides insight into how the clock drives overt rhythms and what to fix when the
circadian system is disrupted (i.e. during shift work). Circadian time coded in the rhythmic
regulation of “clock gene” expression in a negative feedback loop system. Critical to this timing
system is the circadian degradation of rhythmically abundant clock proteins, however these
mechanisms have remained elusive. We have begun elucidating these mechanisms by
developing a novel functional screening approach designed to identify which E3 ubiquitin
ligases degrade which clock proteins. Screen data on three clockwork targets indicate this
approach is sensitive and specific, thus operating as we hoped. A major goal of the current
application is to continue to screen for and validate E3 ligases for other clockwork proteins as
well as some key rhythmic circadian outputs. We believe identifying these E3 ligases and their
roles in clock function will reveals new potential targets for therapeutic intervention of clock-
related disorders.
 The first screen hit we have recovered, Siah2, has revealed remarkable and unexpected
new insights into both clock function and how the clock regulates metabolism. We found that
female mice lacking a functional Siah2 gene lost a mechanism that “protects” against diet-
induced obesity. This appears to be due to a female-specific role in the core circadian clock.
These results suggest, for the first time, that female-specific clockwork mechanisms exist, and
that they contribute directly to female-specific biology. Unfortunately, the vast majority of
circadian data are from male mice. Therefore, we now plan to reassess clock function and
circadian rhythm regulation in females to further identify and define the sex-specific clockwork
mechanisms to provide a background for examining the role of Siah2 in female clocks.
Understanding sex-differences in circadian clock functions will be critical as the field develops
circadian-based therapeutics.

## Key facts

- **NIH application ID:** 10387535
- **Project number:** 3R35GM127044-04S1
- **Recipient organization:** MOREHOUSE SCHOOL OF MEDICINE
- **Principal Investigator:** JASON P DEBRUYNE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $245,775
- **Award type:** 3
- **Project period:** 2021-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387535

## Citation

> US National Institutes of Health, RePORTER application 10387535, Roles of protein degradation in the circadian clock (3R35GM127044-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10387535. Licensed CC0.

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