title: mRNA turnover rate limits siRNA and microRNA efficacy.
abstract: The microRNA pathway participates in basic cellular processes and its discovery has enabled the development of si/shRNAs as powerful investigational tools and potential therapeutics. Based on a simple kinetic model of the mRNA life cycle, we hypothesized that mRNAs with high turnover rates may be more resistant to RNAi-mediated silencing. The results of a simple reporter experiment strongly supported this hypothesis. We followed this with a genome-wide scale analysis of a rich corpus of experiments, including RT-qPCR validation data for thousands of siRNAs, siRNA/microRNA overexpression data and mRNA stability data. We find that short-lived transcripts are less affected by microRNA overexpression, suggesting that microRNA target prediction would be improved if mRNA turnover rates were considered. Similarly, short-lived transcripts are more difficult to silence using siRNAs, and our results may explain why certain transcripts are inherently recalcitrant to perturbation by small RNAs.
authors.affiliation: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. larsson@cbio.mskcc.org
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Debora
authors.initials: D
authors.lastname: Marks
mesh_terms: D002460:Cell Line; D015870:Gene Expression; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering