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
Affiliations
Aris T. Alexandrou
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA; Department of Natural and Quantitative Sciences, Holy Cross College, Notre Dame, IN 46556, USA
Yixin Duan
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Shanxiu Xu
Department of Surgery, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA
Clifford Tepper
Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA
Ming Fan
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Jason Tang
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Jonathan Berg
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Wassim Basheer
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Tyler Valicenti
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Paul F. Wilson
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Matthew A. Coleman
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Andrew T. Vaughan
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA
Loning Fu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
David J. Grdina
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA
Jefferey Murley
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA
Aijun Wang
Department of Surgery, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA
Gayle Woloschak
Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60637, USA
Jian Jian Li
Department of Radiation Oncology, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA; NCI-designated Comprehensive Cancer Center, University of California at Davis, 4501 X Street, Sacramento, CA 95817, USA; Corresponding author
Summary: 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 (Per2def) 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 Per2wt 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.
