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

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

1,2,* , 2
,
3
,
3
 and
1,*
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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Abstract

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 3.0).

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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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