The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α

Elitsa Y Dimova; Mirza Jakupovic; Kateryna Kubaichuk; Daniela Mennerich; Tabughang Franklin Chi; Filippo Tamanini; Małgorzata Oklejewicz; Jens Hänig; Nadiya Byts; Kari A Mäkelä; Karl-Heinz Herzig; Peppi Koivunen; Ines Chaves; Gijsbertus van der Horst; Thomas Kietzmann

doi:10.1016/j.isci.2019.02.027

The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α

iScience. 2019 Mar 29:13:284-304. doi: 10.1016/j.isci.2019.02.027. Epub 2019 Mar 1.

Authors

Affiliations

¹ Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O. Box 3000, 90014 Oulu, Finland. Electronic address: elitsa.dimova@oulu.fi.
² Department of Biochemistry, University of Kaiserslautern, 67663 Kaiserslautern, Germany.
³ Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O. Box 3000, 90014 Oulu, Finland.
⁴ Department of Molecular Genetics, Erasmus University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands.
⁵ Novartis Pharma GmbH, 97082 Würzburg, Germany.
⁶ Biocenter Oulu, Department of Physiology, University of Oulu, 90014 Oulu, Finland.
⁷ Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O. Box 3000, 90014 Oulu, Finland. Electronic address: thomas.kietzmann@oulu.fi.

Abstract

The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1α via its tail region. Subsequently, CRY1 reduces HIF-1α half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis.

Keywords: Biochemistry; Biological Sciences; Cell Biology; Molecular Biology.