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Updated: Aug 22, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout
Seref Gul1,2, Yasemin Kubra Akyel3,4, Zeynep Melis Gul5
1Department of Chemical and Biological Engineering, Koc University, 34450, Sariyer-Istanbul, Turkey.
Abstract:
Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53-/- mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.
Insights
Researchers discovered M47, a molecule that reduces Cryptochrome 1 (CRY1) levels, extending circadian period length and enhancing cancer cell apoptosis. This finding suggests M47 as a potential therapeutic for p53-mutated cancers.
Area of Science:
- Molecular Biology
- Chronobiology
- Cancer Research
Background:
- Cryptochromes (CRY1) regulate mammalian circadian rhythms.
- The impact of reduced CRY1 on circadian rhythm and apoptosis is unclear.
Purpose of the Study:
- To investigate the effect of a novel molecule (M47) on CRY1 levels and its downstream consequences.
- To explore M47's potential in cancer therapy.
Main Methods:
- In vitro and in vivo destabilization of CRY1 using M47.
- Assessment of CRY1 ubiquitination and degradation.
- Analysis of circadian period length in U2OS Bmal1-dLuc cells.
- Subcellular fractionation in mouse liver.
- Evaluation of oxaliplatin-induced apoptosis in p53-null cells.
- Lifespan studies in p53-/- mice.
Main Results:
- M47 selectively enhanced CRY1 degradation via increased ubiquitination.
- M47 treatment increased the circadian period length in cells.
- M47 promoted CRY1 degradation in the nucleus of mouse liver cells.
- Reduced CRY1 levels enhanced oxaliplatin-induced apoptosis in p53-null cancer cells.
- M47 administration extended the median lifespan of p53-/- mice by approximately 25%.
Conclusions:
- M47 effectively reduces CRY1 levels, impacting circadian rhythm and promoting apoptosis.
- M47 demonstrates potential as a therapeutic agent for cancers with p53 mutations.
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