Abstract LB-184: Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics

Abstract

Abstract Circadian clocks are intimately involved in the homeostatic maintenance of metabolic and physiological processes that may have increasingly important roles to enhance bone marrow transplantation success in cancer patients; to protect normal tissue surrounding tumors from the harmful effects of radio/chemotherapy; and to enhance the quality of diet and sleep for astronauts during space exploration. Herein, we report that expression of PERIOD2 (PER2; a core circadian clock component and “the inherent driver” of radioprotection) is required for adaptive protection against environmental radiation stress. PER2 expression is induced by exposure to low dose radiation (LDR; 10cGy) and siRNA blockade of PER2 ablates LDR-induced adaptive radioprotection. In addition, melatonin (N-acetyl-5-methoxytryptamine), a natural anti-oxidant and hypothalamic circadian synchronizer, stimulates PER2 expression and confers mice radioprotection through weight maintenance and increased survival. LDR-induced PER2 transcription is regulated by NF-κB and β-catenin and is released from phospho-glycogen synthase kinase-3ß (p-GSK3ß) in the WNT/β-catenin pathway. Unbound β-catenin interacts with the TCF/LEF domain on the Per2 promoter to promote feed-forward PER2-pGSK3β complex formation. Mitochondrial bioenergetics measured by oxygen consumption and ATP generation was attenuated in bone marrow isolated from PER2 mutant (Per2m/m) mice. Furthermore, RNA-seq profiling of bone marrow-derive progenitor hematopoietic stem cells (BM-pHSCs; Lin-/Sca1+/cKit+; LSK) cells isolated form LDR-treated wild-type (WT) versus Per2m/m mice showed a cluster of genes involved in mitochondrial bioenergetics and DNA repair capacity. These results demonstrate that a core circadian regulator plays an indispensable role in defending mammalian cells against environmental genotoxic stress through the PER2/β-catenin pathway, a potential therapeutic target to enhance cell survival under radiation. Citation Format: Aris Alexandrou, Ming Fan, Shuaib Juma, Julian Perks, Andrew Vaughan, Clifford Tepper, Loning Fu, Gayle Woloschak, David Grdina. Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-184.