Aris T . Alexandrou
Loning Fu2014, Cancer Research
Circadian deregulation is associated with the development of numerous diseases, including cancer, diabetes, and several neurological disorders. A recent study shows that the onset of carcinogenicity is specifically linked to the time of exposures (day or night) to ultraviolet light and ionizing radiation in mice. This effect is believed to be mediated through radiation-induced DNA damage and deregulation of the WNT/β-Catenin signaling pathway, hence affecting cell survival and proliferation. Results: The current studies aim to elucidate the contribution of a core circadian gene, Period2 (Per2), in the radioprotective response of mice bone marrow. Epithelial cells and mice bone marrow express PER2 in contrast to cancer cells. Bone marrow isolated from Per2 knockout mice exhibit radioresistence to high doses of ionizing radiation (HDIR; 2Gy) compared to wild-type mice controls suggesting that Per2 expression was responsible for radiation-induced cell death. This finding was translated by increased granulocyte-macrophage (GM-CFUs) clonogenic survival and reduced cell apoptosis. Mechanistic analysis showed that Per2 knockout mice bone marrow expressed higher levels of procaspase3 and less expression of active caspase3 after HDIR treatment compared to wild-type mice bone marrow and sham irradiated controls. Furthermore, Per2 knockout mice treated with 12Gy total body radiation (TBIR) showed an 80% survival verses 30% survival in wild-type mice. Whole genome-wide sequencing detected signal transduction pathways reflecting enhanced DNA damage repair capacity in knockout mice bone marrow, hence defining the role of PER2 in the radioresistant phenotype in vivo. Conclusions: This data is the first evidence supporting the critical role of PER2 in protecting mice hematopoietic stem cells (HSCs) from HDIR via enhancement of genes involved in DNA repair signaling networks.