Abstract 5695: Roles of cGAS in DNA damage response

Abstract

Abstract Cytosolic double strand DNAs released from the nucleus or mitochondria produce diverse cellular signals mediated by cyclic GAM-AMP synthase (cGAS) to modulate cell proliferation, metastasis, apoptosis, and necroptosis. However, the role of cGAS has not been fully elucidated when cells are stimulated with DNA damage response such as ultraviolet (UV). In this study, we found that DNA damage by treatment of cisplatin or UVB induced cGAS protein levels. We further found that cisplatin and UVB increased not only endogenous cGAS protein levels, but also ectopic expressed cGAS protein levels. The cGAS protein increase was showed positive correlation with H2AX phosphorylation at Ser139 (γH2AX). Moreover, although UVB stimulation suppressed cell proliferation in both stably expressing mock control (SK-MEL-2-mock) and cGAS in SK-MEL-2 (SK-MEL-2-cGAS) cells, suppression ratio in SK-MEL-2-cGAS cells was reduced compared to SK-MEL-2-mock cells. These results suggested that cGAS may have a potential to cell protection when the cells are stimulated with DNA damage. This hypothesis was supported by that cell proliferation of SK-MEL-2-cGAS cells were 2 folds faster than that of SK-MEL-2-mock cells after UVB stimulation. We further found that living cell population of SK-MEL-2-cGAS cells, which were 80% in no UVB stimulation, was reduced to 37% at 24 h and 34% at 48 h after 2 mJ/cm2 UVB stimulation, while SK-MEL-2-mock cells were reduced to 37% at 24 h and 20% at 48 h after 2 mJ/cm2 UVB stimulation. On the other hand, total cell death about 40% at 24 h and 65% at 48 h in SK-MEL-2-mock cells was reduced about 25% at 24 h and 36% at 48 h in SK-MEL-2-cGAS cells after 2 mJ/cm2 UVB stimulation. Taken together, we concluded that cGAS may play an important role to protect the cells from DNA damage. Citation Format: Weidong Chen, Hyun-Jung An, Ga-Eun Lee, Yong-Yeon Cho. Roles of cGAS in DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5695.