PERIOD 2 regulates low-dose radioprotection via PER2/pGSK3β/β-catenin/Per2 loop

Aris T Alexandrou; Yixin Duan; Shanxiu Xu; Clifford Tepper; Ming Fan; Jason Tang; Jonathan Berg; Wassim Basheer; Tyler Valicenti; Paul F Wilson; Matthew A Coleman; Andrew T Vaughan; Loning Fu; David J Grdina; Jefferey Murley; Aijun Wang; Gayle Woloschak; Jian Jian Li

doi:10.1016/j.isci.2022.105546

PERIOD 2 regulates low-dose radioprotection via PER2/pGSK3β/β-catenin/Per2 loop

iScience. 2022 Nov 9;25(12):105546. doi: 10.1016/j.isci.2022.105546. eCollection 2022 Dec 22.

Authors

Aris T Alexandrou^{1

2}, Yixin Duan¹, Shanxiu Xu³, Clifford Tepper⁴, Ming Fan¹, Jason Tang¹, Jonathan Berg¹, Wassim Basheer¹, Tyler Valicenti¹, Paul F Wilson¹, Matthew A Coleman¹, Andrew T Vaughan¹, Loning Fu⁵, David J Grdina⁶, Jefferey Murley⁶, Aijun Wang³, Gayle Woloschak⁷, Jian Jian Li^{1

8}

Affiliations

¹ Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA.
² Department of Natural and Quantitative Sciences, Holy Cross College, Notre Dame, IN 46556, USA.
³ Department of Surgery, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
⁴ Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA.
⁵ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
⁷ Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60637, USA.
⁸ NCI-designated Comprehensive Cancer Center, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA.

Abstract

During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection. Herein, we demonstrate that radiosensitivity is increased in mice with the deficient Period 2 gene (Per2^def) due to impaired DNA repair and mitochondrial function in progenitor bone marrow hematopoietic stem cells and monocytes. Per2 induction and radioprotection are also identified in LDR-treated Per2^wt mouse cells and in human skin (HK18) and breast (MCF-10A) epithelial cells. LDR-boosted PER2 interacts with pGSK3β(S9) which activates β-catenin and the LEF/TCF mediated gene transcription including Per2 and genes involved in DNA repair and mitochondrial functions. This study demonstrates that PER2 plays an active role in LDR adaptive radioprotection via PER2/pGSK3β/β-catenin/Per2 loop, a potential target for protecting normal cells from radiation injury.

Keywords: Biological sciences; cell biology; molecular biology.

Abstract

Grants and funding