PT  - JOURNAL ARTICLE
AU  - Seref Gul
AU  - Yasemin Kubra Akyel
AU  - Zeynep Melis Gul
AU  - Safak Isin
AU  - Tuba Korkmaz
AU  - Saba Selvi
AU  - Ibrahim Danis
AU  - Ozgecan Savlug Ipek
AU  - Fatih Aygenli
AU  - Ali Cihan Taskin
AU  - Nuri Ozturk
AU  - Narin Ozturk
AU  - Durişehvar Özer Ünal
AU  - Mustafa Guzel
AU  - Metin Turkay
AU  - Alper Okyar
AU  - Ibrahim Halil Kavakli
TI  - Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
AID  - 10.1101/2021.07.21.453206
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.21.453206
4099  - http://biorxiv.org/content/early/2021/07/21/2021.07.21.453206.short
4100  - http://biorxiv.org/content/early/2021/07/21/2021.07.21.453206.full
AB  - Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous level of the CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis is unknown. Here, we discovered a molecule that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The small molecule, called M47, selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and the period of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 enhanced degradation rate of the CRY1 level in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced cisplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Finally, systemic repetitive administration of M47 increased the median lifespan of p53−/− mice by ~25%. Collectively our data suggest that M47 is a very promising molecule to treat forms of cancer depending on the p53 mutation.Competing Interest StatementThe authors have declared no competing interest.