Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

Seref Gul, Yasemin Kubra Akyel, Zeynep Melis Gul, Safak Isin, Onur Ozcan, Tuba Korkmaz, Saba Selvi, Ibrahim Danis, Ozgecan Savlug Ipek, Fatih Aygenli, Ali Cihan Taskin, Büşra Aytül Akarlar, Nurhan Ozlu, Nuri Ozturk, Narin Ozturk, Durişehvar Özer Ünal, Mustafa Guzel, Metin Turkay, Alper Okyar and Ibrahim Halil Kavakli ()
Additional contact information
Seref Gul: Koc University
Yasemin Kubra Akyel: İstanbul University
Zeynep Melis Gul: Koc University
Safak Isin: Koc University
Onur Ozcan: Koc University
Tuba Korkmaz: Gebze Technical University, Gebze
Saba Selvi: Gebze Technical University, Gebze
Ibrahim Danis: İstanbul University
Ozgecan Savlug Ipek: İstanbul Medipol University
Fatih Aygenli: Gebze Technical University, Gebze
Ali Cihan Taskin: Koc University, Rumelifeneri yolu
Büşra Aytül Akarlar: Koc University
Nurhan Ozlu: Koc University
Nuri Ozturk: Gebze Technical University, Gebze
Narin Ozturk: İstanbul University
Durişehvar Özer Ünal: İstanbul University
Mustafa Guzel: İstanbul Medipol University
Metin Turkay: Koc University
Alper Okyar: İstanbul University
Ibrahim Halil Kavakli: Koc University

Nature Communications, 2022, vol. 13, issue 1, 1-17

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-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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34582-1

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DOI: 10.1038/s41467-022-34582-1

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