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Elife. 2018 Jul 31;7. pii: e36362. doi: 10.7554/eLife.36362.

Control of the polyamine biosynthesis pathway by G2-quadruplexes.

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Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
Biomolecular NMR spectroscopy platform, ETH Zurich, Zurich, Switzerland.


G-quadruplexes are naturally-occurring structures found in RNAs and DNAs. Regular RNA G-quadruplexes are highly stable due to stacked planar arrangements connected by short loops. However, reports of irregular quadruplex structures are increasing and recent genome-wide studies suggest that they influence gene expression. We have investigated a grouping of G2-motifs in the UTRs of eight genes involved in polyamine biosynthesis, and concluded that several likely form novel metastable RNA G-quadruplexes. We performed a comprehensive biophysical characterization of their properties, comparing them to a reference G-quadruplex. Using cellular assays, together with polyamine-depleting and quadruplex-stabilizing ligands, we discovered how some of these motifs regulate and sense polyamine levels, creating feedback loops during polyamine biosynthesis. Using high-resolution 1H-NMR spectroscopy, we demonstrated that a long-looped quadruplex in the AZIN1 mRNA co-exists in salt-dependent equilibria with a hairpin structure. This study expands the repertoire of regulatory G-quadruplexes and demonstrates how they act in unison to control metabolite homeostasis.


NMR; RNA; biochemistry; chemical biology; human; polyamine; pyridostatin; quadruplex; thioflavin

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