Recent advances in radiobiology with respect to pleiotropic aspects of tissue reaction

Abstract

DNA double-strand breaks (DSBs) induced by ionizing radiation are the major cause of cell death, leading to tissue/organ injuries, which is a fundamental mechanism underlying the development of tissue reaction. Since unscheduled senescence, predominantly induced among epithelial tissues/organs, is one of the major modes of cell death in response to radiation exposure, its role in tissue reaction has been extensively studied, and it has become clear that senescence-mediated secretion of soluble factors is an indispensable component of the manifestation of tissue reaction. Recently, an unexpected link between cytoplasmic DSBs and innate immunity was discovered. The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) results in the stimulation of the cGAS-stimulator of interferon genes (STING) pathway, which has been shown to regulate the transactivation of a variety of secretory factors that are the same as those secreted from senescent cells. Furthermore, it has been proven that cGAS-STING pathway also mediates execution of the senescence process by itself. Hence, an autocrine/paracrine feedback loop has been discussed in previous literature in relation to its effect on the tissue microenvironment. As the tissue microenvironment plays a crucial role in cancer development, tissue reaction could be involved in the late health effects caused by radiation exposure. In this paper, the novel findings in radiation biology, which should provide a better understanding of the mechanisms underlying radiation-induced carcinogenesis, are overviewed.

Keywords: cGAS-STING pathway; cancer risk; radiation; tissue reaction.

Fig. 1.

Caspase-dependent DNA fragmentation in micronuclei. Exponentially growing normal human diploid cells were exposed to 1 Gy of γ-rays and incubated for a further 24 h before fixation with methanol. The samples were then incubated with anti-phosphorylated histone H2AX mouse antibody and anti-53BP1 rabbit antibody, which were detected by Alexa488-conjugated anti-mouse antibody and Alexa555-conjugated anti-rabbit antibody, respectively. The cells were treated with caspase-8 inhibitor (middle row) or with caspase-3 inhibitor (bottom row) 30 min before irradiation. The white arrow heads indicate micronnuclei. Scale bar, 10 μm.

Fig. 2.

cGAS–STING signaling pathway. Cytoplasmic double-stranded DNA activates the cGAS–STING signaling pathway. cGAS is able to recognize cytoplasmic double-stranded DNA through its unique structure, thereby turning on the enzymatic activity catalyzing the cyclization of AMP and GMP, which results in the formation of cGAMP. cGAMP then binds to STING and activates it as an adaptor, which modulates transcription through IRF3 and NF-κB. Thus, the cGAS–STING signaling pathway plays a critical role in senescence induction after radiation exposure.