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¹ Key Laboratory of Molecular Biology for Infectious Diseases of the State Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
² Hygiene Toxicology Department, Preventive Medicine College, Third Military Medical University, Chongqing 400038, People's Republic of China

Correspondence to Kai-Fu Tang: tang_kaifu{at}yahoo.com.cn or tangkaifu{at}hotmail.com

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.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; ATR, ATM- and Rad3-related; BTG3, B cell translocation gene 3; Chk1, checkpoint kinase 1; DSB, DNA double-strand break; ecc, extrachromosomal circular; ERG1, early growth response 1; GADD45, growth arrest– and DNA damage–inducible gene; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MICA, major histocompatibility complex class I–related gene A; MICB, major histocompatibility complex class I–related gene B; NK, natural killer; PKR, protein kinase R; RPA70, replication protein A 70; ULBP, UL16-binding protein.

© 2008 Tang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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