Article

A potential role for RNA interference in controlling the activity of the human LINE-1 retrotransposon

Division of Molecular Biology, Beckman Research Institute of the City of Hope 1450 East Duarte Road, Duarte, CA 91010-3011, USA.
Nucleic Acids Research (Impact Factor: 9.11). 02/2005; 33(3):846-56. DOI: 10.1093/nar/gki223
Source: PubMed

ABSTRACT Long interspersed nuclear elements (LINE-1 or L1) comprise 17% of the human genome, although only 80-100 L1s are considered retrotransposition-competent (RC-L1). Despite their small number, RC-L1s are still potential hazards to genome integrity through insertional mutagenesis, unequal recombination and chromosome rearrangements. In this study, we provide several lines of evidence that the LINE-1 retrotransposon is susceptible to RNA interference (RNAi). First, double-stranded RNA (dsRNA) generated in vitro from an L1 template is converted into functional short interfering RNA (siRNA) by DICER, the RNase III enzyme that initiates RNAi in human cells. Second, pooled siRNA from in vitro cleavage of L1 dsRNA, as well as synthetic L1 siRNA, targeting the 5'-UTR leads to sequence-specific mRNA degradation of an L1 fusion transcript. Finally, both synthetic and pooled siRNA suppressed retrotransposition from a highly active RC-L1 clone in cell culture assay. Our report is the first to demonstrate that a human transposable element is subjected to RNAi.

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    • "Secondly, retrotransposable elements are also susceptible to post-transcriptional regulation. For instance, endogenously encoded small interfering RNAs have been shown to reduce L1 retrotransposition in vitro (Soifer et al., 2005; Yang and Kazazian, 2006). Additionally, L1 transcripts that contain multiple polyadenylation signals lead to premature polyadenylation , resulting in the attenuation of L1 activity via truncation of its full-length transcripts (Perepelitsa-Belancio and Deininger, 2003). "
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    • "). In human cell lines, transfected exogenous siRNAs can limit L1 expression (Soifer et al., 2005). But while TE-associated endogenous siRNAs have been reported in mammals, their formal involvement in host defense against TE invasion is still lacking. "
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    • "However, the potential role of RNAi as a natural antiviral defence mechanism in mammalian cells remains controversial. The characteristic of antiviral RNAi—that is, accumulation of virusderived siRNAs—could not be identified in infected cells (Pfeffer et al, 2004); however, such molecules have been described more recently for several endogenous and exogenous viruses, including human immunodeficiency virus type 1 (HIV-1; Bennasser et al, 2005; Soifer et al, 2005; Yang & Kazazian, 2006; Parameswaran et al, 2008), and yet the significance of these findings is still being debated (Lin & Cullen, 2007). There is accumulating evidence that mammalian cells use microRNAs (miRNAs) to control viruses (Berkhout & Jeang, 2007). "
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