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

Author

Listed:
  • Seref Gul

    (Koc University
    İstanbul University)

  • Yasemin Kubra Akyel

    (İstanbul University
    Istanbul Medipol 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
    İstanbul University Drug Research and Application Center (ILAM))

  • Ozgecan Savlug Ipek

    (İstanbul Medipol University
    Yildiz Technical 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
    İstanbul University Drug Research and Application Center (ILAM))

  • Mustafa Guzel

    (İstanbul Medipol University
    İstanbul Medipol University)

  • Metin Turkay

    (Koc University)

  • Alper Okyar

    (İstanbul University)

  • Ibrahim Halil Kavakli

    (Koc University
    Koc University)

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.

Suggested Citation

  • 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 , 2022. "Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34582-1
    DOI: 10.1038/s41467-022-34582-1
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    References listed on IDEAS

    as
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