Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
Şeref Gül, Yasemin Kübra Akyel, Zeynep Melis Gül, Safak Isin, Onur Özcan, Tuba Korkmaz, Saba Selvi, Ibrahim Danis, Özgecan Şavluğ İpek, Fatih Aygenli, Ali Cihan Taşkın, Büşra Aytül Akarlar, Nurhan Özlü, Nuri Öztürk, Narin Öztürk, Durişehvar Özer Ünal, Mustafa Güzel, Metin Türkay, Alper Okyar, İbrahim Halil Kavaklı
Abstract
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 -d Luc 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.