Circadian Protein PERIOD 2 Regulates Adaptive Radioprotection via PER2/pGSK3β/β-Catenin/Per2 Loop

Circadian rhythm (CR) and low-dose radiation (LDR) evident on Earth’s surface may have coordinated in the evolution of original life forms. Disturbed CR or overexposure to radiation are well documented to cause aging and diseases, and both tumor and normal tissues show CR-related radiosensitivity. However, it is unclear how CR proteins participate in the LDR-mediated adaptive radioprotection. Herein, we demonstrate that mice carrying a deficient Period2 gene (C57BL-Per2def) a core CR regulator were highly radiosensitive with reduced ability in DNA repair and mitochondrial metabolism. Unlike Per2def cells, Per2wt human and mouse cells were LDR responsive with induced radioprotection and Per2 expression. PER2 interacted with p GSK3β leading to β -catenin activation that further transactivated Per2 and other prosurvival genes for a prosurvival potential. These results indicate that PER2 functions in the communication between CR and LDR signaling pathway, the PER2/pGSK3β/β-catenin/Per2 loop is a therapeutic target to protect normal tissue in cancer radiotherapy.