Period 2 Regulates Low-Dose Radioprotection via PER2/pGSK3β/β-Catenin/Per2 Loop

Authors

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

Publication Date

12-22-2022

Journal

iScience

DOI

10.1016/j.isci.2022.105546

PMID

36465103

PMCID

PMC9708791

PubMedCentral® Posted Date

11-9-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Biological sciences, cell biology, molecular biology

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 (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.

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