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Biochemistry. 2015 Dec 8;54(48):7067-78. doi: 10.1021/acs.biochem.5b00574. Epub 2015 Nov 19.

The RNA Stem-Loop to G-Quadruplex Equilibrium Controls Mature MicroRNA Production inside the Cell.

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Chemical and Systems Biology Unit, CSIR-Institute of Genomics and Integrative Biology , Mathura Road, New Delhi 110020, India.
CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 400008, India.
Solution Equilibria and Chemometrics Group, Department of Analytical Chemistry, University of Barcelona , Diagonal 645, E-08028 Barcelona, Spain.
Academy of Scientific and Innovative Research (AcSIR) , Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.


The biological role of the existence of overlapping structures in RNA is possible yet remains very unexplored. G-Rich tracts of RNA form G-quadruplexes, while GC-rich sequences prefer stem-loop structures. The equilibrium between alternate structures within RNA may occur and influence its functionality. We tested the equilibrium between G-quadruplex and stem-loop structure in RNA and its effect on biological processes using pre-miRNA as a model system. Dicer enzyme recognizes canonical stem-loop structures in pre-miRNA to produce mature miRNAs. Deviation from stem-loop leads to deregulated mature miRNA levels, providing readout of the existence of an alternate structure per se G-quadruplex-mediated structural interference in miRNA maturation. In vitro analysis using beacon and Dicer cleavage assays indicated that mature miRNA levels depend on relative amounts of K(+) and Mg(2+) ions, suggesting an ion-dependent structural shift. Further in cellulo studies with and without TmPyP4 (RNA G-quadruplex destabilizer) demonstrated that miRNA biogenesis is modulated by G-quadruplex to stem-loop equilibrium in a subset of pre-miRNAs. Our combined analysis thus provides evidence of the formation of noncanonical G-quadruplexes in competition with canonical stem-loop structure inside the cell and its effect on miRNA maturation in a comprehensive manner.

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