Nucleic Acids Research Advance Access published online on March 27, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm133
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Distance constraints between microRNA target sites dictate efficacy and cooperativity
1Division of Molecular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA, 2Interagon AS, Laboratoriesenteret, NO-7489 Trondheim, Norway, 3Department of Computer and Information Science, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway and 4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway
*To whom correspondence should be addressed. Tel: +1 626 301 8360; Fax: +1 626 301 8271; Email: jrossi{at}coh.org
Received November 21, 2006. Revised February 16, 2007. Accepted February 19, 2007.
MicroRNAs (miRNAs) have the potential to regulate the expression of thousands of genes, but the mechanisms that determine whether a gene is targeted or not are poorly understood. We studied the genomic distribution of distances between pairs of identical miRNA seeds and found a propensity for moderate distances greater than about 13 nt between seed starts. Experimental data show that optimal down-regulation is obtained when two seed sites are separated by between 13 and 35 nt. By analyzing the distance between seed sites of endogenous miRNAs and transfected small interfering RNAs (siRNAs), we also find that cooperative targeting of sites with a separation in the optimal range can explain some of the siRNA off-target effects that have been reported in the literature.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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