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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.

Author information

1
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
2
Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
3
Biomolecular NMR spectroscopy platform, ETH Zurich, Zurich, Switzerland.

Abstract

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.

KEYWORDS:

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

PMID:
30063205
PMCID:
PMC6067879
DOI:
10.7554/eLife.36362
[Indexed for MEDLINE]
Free PMC Article

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