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Int. J. Mol. Sci. 2013, 14(5), 9305-9318; doi:10.3390/ijms14059305

Off-Target Effect of Endogenous siRNA Derived from RMRP in Human Cells

1,2,* , 2
1 Division of Cancer Stem Cell, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan 2 Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan 3 RIKEN Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
* Authors to whom correspondence should be addressed.
Received: 28 February 2013 / Revised: 16 April 2013 / Accepted: 17 April 2013 / Published: 29 April 2013
(This article belongs to the Special Issue Molecular Cut and Paste)
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Endogenous siRNAs (endo-siRNAs) are key regulators of RNA silencing in plants and worms; however, the biogenesis and function of endogenous siRNAs in mammals remain largely unknown. We previously demonstrated that human telomerase reverse transcriptase produces a self-targeting endogenous siRNA from non-coding RMRP RNA via RNA-dependent RNA polymerase (RdRP) activity. Here, we investigated whether the endo-siRNA derived from RMRP targets other genes in addition to RMRP. Four algorithms for microRNA target prediction were used to identify possible targets of the endo-siRNA, and the phytanoyl-CoA hydroxylase-interacting protein-like gene (PHYHIPL) was identified as the most promising candidate. The 3' UTR of PHYHIPL was found to contain three possible target sites with perfect seed pairing; deletion of each of these sites resulted in recovery of upstream luciferase expression. In addition, sequence-specific inhibition of the RMRP-derived endo-siRNA increased expression of PHYHIPL mRNA. The results described here suggest that the endo-siRNA uses silencing mechanisms that are similar to those used by microRNAs for gene silencing. To our knowledge, this study is the first confirmation of the off-target effect of human endogenous siRNA produced by RdRP activity.
Keywords: endogenous siRNA; hTERT; off-targeting; RNA-dependent RNA polymerase endogenous siRNA; hTERT; off-targeting; RNA-dependent RNA polymerase
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Maida, Y.; Kyo, S.; Lassmann, T.; Hayashizaki, Y.; Masutomi, K. Off-Target Effect of Endogenous siRNA Derived from RMRP in Human Cells. Int. J. Mol. Sci. 2013, 14, 9305-9318.

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