The cAMP signaling system inhibits the repair of 纬-ray-induced DNA damage by promoting Epac1-mediated proteasomal degradation of XRCC1 protein in human lung cancer cells

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• 作者：Eun-Ah Cho ; Yong-Sung Juhnn ; ^{juhnn@snu.ac.kr}
• 关键词：8-pCPT-2&prime ; -O-Me-cAMP ; 8-(4-chlorophenylthio)-2&prime ; -O-methyladenosine-3&prime ; 5&prime ; -cyclic monophosphate ; Epac ; PKA ; cAMP-dependent protein kinase ; XRCC1 ; X-ray repair cross-complementing protein 1
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：1 June, 2012
• 卷：422
• 期：2
• 页码：256-262
• 文件大小：643 K

摘要

Cyclic AMP is involved in the regulation of metabolism, gene expression, cellular growth and proliferation. Recently, the cAMP signaling system was found to modulate DNA-damaging agent-induced apoptosis by regulating the expression of Bcl-2 family proteins and inhibitors of apoptosis. Thus, we hypothesized that the cAMP signaling may modulate DNA repair activity, and we investigated the effects of the cAMP signaling system on 纬-ray-induced DNA damage repair in lung cancer cells. Transient expression of a constitutively active mutant of stimulatory G protein (G伪sQL) or treatment with forskolin, an adenylyl cyclase activator, augmented radiation-induced DNA damage and inhibited repair of the damage in H1299 lung cancer cells. Expression of G伪sQL or treatment with forskolin or isoproterenol inhibited the radiation-induced expression of the XRCC1 protein, and exogenous expression of XRCC1 abolished the DNA repair-inhibiting effect of forskolin. Forskolin treatment promoted the ubiquitin and proteasome-dependent degradation of the XRCC1 protein, resulting in a significant decrease in the half-life of the protein after 纬-ray irradiation. The effect of forskolin on XRCC1 expression was not inhibited by PKA inhibitor, but 8-pCPT-2鈥?O-Me-cAMP, an Epac-selective cAMP analog, increased ubiquitination of XRCC1 protein and decreased XRCC1 expression. Knockdown of Epac1 abolished the effect of 8-pCPT-2鈥?O-Me-cAMP and restored XRCC1 protein level following 纬-ray irradiation. From these results, we conclude that the cAMP signaling system inhibits the repair of 纬-ray-induced DNA damage by promoting the ubiquitin-proteasome dependent degradation of XRCC1 in an Epac-dependent pathway in lung cancer cells.