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Distinct differences in metal ion specificity of RNA and DNA G-quadruplexes

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Abstract

RNA G-quadruplexes, as their well-studied DNA analogs, require the presence of cations to fold and remain stable. This is the first comprehensive study on the interaction of RNA quadruplexes with metal ions. We investigated the formation and stability of two highly conserved and biologically relevant RNA quadruplex-forming sequences (24nt-TERRA and 18nt-NRAS) in the presence of several monovalent and divalent metal ions, namely Li+, Na+, K+, Rb+, Cs+, NH4 +, Mg2+, Ca2+, Sr2+, and Ba2+. Circular dichroism was used to probe the influence of these metal ions on the folded fraction of the parallel G-quadruplexes, and UV thermal melting experiments allowed to assess the relative stability of the structures in each cationic condition. Our results show that the RNA quadruplexes are more stable than their DNA counterparts under the same buffer conditions. We have observed that the addition of mainly Na+, K+, Rb+, NH4 +, as well as Sr2+ and Ba2+ in water, shifts the equilibrium to the folded quadruplex form, whereby the NRAS sequence responds stronger than TERRA. However, only K+ and Sr2+ lead to a significant increase in the stability of the folded structures, which is consistent with their coordination to the O6 atoms from the G-quartet guanosines. Compared to the respective DNA motives, dNRAS and htelo, the RNA sequences are not stabilized by Na+ ions. Finally, the difference in response between NRAS and TERRA, as well as to the corresponding DNA sequences with respect to different metal ions, could potentially be exploited for selective targeting purposes.

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Abbreviations

CD:

Circular dichroism

[θ]:

Molar ellipticity

G4:

G-Quadruplex

htelo:

Human telomere

M+ :

Monovalent cation

M2+ :

Divalent cation

MOPS:

3-(N-morpholino)propanesulfonic acid

NRAS:

Neuroblastoma rat sarcoma viral oncogene homolog

nt:

Nucleotide

TERRA:

Telomeric repeat-containing RNA

T m :

Melting temperature

UTR:

Untranslated region

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Acknowledgments

This work was supported by the European Research Council (ERC Starting Grant MIRNA No. 259092 to R.K.O.S.) and the Forschungskredit grant of the University of Zurich (FK-13-090 to H.G.M, FK-14-096 and FK-15-095 to R.B.). We are very thankful for further financial support by the Swiss National Science Foundation (Project Funding to R.K.O.S. and Ambizione Fellowship PZ00P2_136726 to D.D.) and the Swiss State Secretariat for Education and Research (COST Action CM1105). H.G.M. thanks Prof. Ramon Vilar (Imperial College London) for encouraging discussions and Dr. Alicia Domínguez-Martín for comments on the manuscript.

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  1. Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Helena Guiset Miserachs, Daniela Donghi, Richard Börner, Silke Johannsen & Roland K. O. Sigel

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  1. Helena Guiset Miserachs
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Correspondence to Richard Börner, Silke Johannsen or Roland K. O. Sigel.

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Guiset Miserachs, H., Donghi, D., Börner, R. et al. Distinct differences in metal ion specificity of RNA and DNA G-quadruplexes. J Biol Inorg Chem 21, 975–986 (2016). https://doi.org/10.1007/s00775-016-1393-4

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