Decreased Dicer expression elicits DNA damage and up-regulation of MICA and MICB |
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Authors: | Tang Kai-Fu Ren Hong Cao Jia Zeng Gui-Li Xie Jing Chen Min Wang Lu He Cai-Xia |
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Institution: | Key Laboratory of Molecular Biology for Infectious Diseases of the State Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China. tang_kaifu@yahoo.com.cn |
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Abstract: | RNA interference (RNAi) acts constitutively to silence the innate immune response, and innate immunity genes are misregulated in Dicer-deficient Caenorhabditis elegans. Here, we show that inhibition of Dicer expression by RNAi in human cells up-regulates major histocompatibility complex class I-related molecules A and B (MICA and MICB). MICA and MICB are innate immune system ligands for the NKG2D receptor expressed by natural killer cells and activated CD8(+)T cells. We reveal that knockdown of Dicer elicits DNA damage. Up-regulation of MICA and MICB by Dicer knockdown is prevented by pharmacologic or genetic inhibition of DNA damage pathway components, including ataxia telangiectasia mutated (ATM) kinase, ATM- and Rad3-related kinase, or checkpoint kinase 1. Therefore we conclude that up-regulation of MICA and MICB is the result of DNA damage response activation caused by Dicer knockdown. Our results suggest that RNAi is indirectly linked to the human innate immune system via the DNA damage pathway. |
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