Small Antisense Oligonucleotides Against G-quadruplexes: Specific MRNA Translational Switches

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2014 Dec 17

PMID 25510493

Citations 20

Authors

Samuel G Rouleau

Jean-Denis Beaudoin

Martin Bisaillon

Jean-Pierre Perreault

Affiliations

Soon will be listed here.

Abstract

G-quadruplexes (G4) are intricate RNA structures found throughout the transcriptome. Because they are associated with a variety of biological cellular mechanisms, these fascinating structural motifs are seen as potential therapeutic targets against many diseases. While screening of chemical compounds specific to G4 motifs has yielded interesting results, no single compound successfully discriminates between G4 motifs based on nucleotide sequences alone. This level of specificity is best attained using antisense oligonucleotides (ASO). Indeed, oligonucleotide-based strategies are already used to modulate DNA G4 folding in vitro. Here, we report that, in human cells, the use of short ASO to promote and inhibit RNA G4 folding affects the translation of specific mRNAs, including one from the 5'UTR of the H2AFY gene, a histone variant associated with cellular differentiation and cancer. These results suggest that the relatively high specificity of ASO-based strategies holds significant potential for applications aimed at modulating G4-motif folding.

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References

Beaudoin J, Perreault J . Exploring mRNA 3'-UTR G-quadruplexes: evidence of roles in both alternative polyadenylation and mRNA shortening. Nucleic Acids Res. 2013; 41(11):5898-911. PMC: 3675481. DOI: 10.1093/nar/gkt265. View

Bochman M, Paeschke K, Zakian V . DNA secondary structures: stability and function of G-quadruplex structures. Nat Rev Genet. 2012; 13(11):770-80. PMC: 3725559. DOI: 10.1038/nrg3296. View

Petersen M, Wengel J . LNA: a versatile tool for therapeutics and genomics. Trends Biotechnol. 2003; 21(2):74-81. DOI: 10.1016/S0167-7799(02)00038-0. View

Creppe C, Janich P, Cantarino N, Noguera M, Valero V, Musulen E . MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells. Mol Cell Biol. 2012; 32(8):1442-52. PMC: 3318583. DOI: 10.1128/MCB.06323-11. View

Fisette J, Montagna D, Mihailescu M, Wolfe M . A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing. J Neurochem. 2012; 121(5):763-73. PMC: 3342435. DOI: 10.1111/j.1471-4159.2012.07680.x. View

Allerson C, Sioufi N, Jarres R, Prakash T, Naik N, Berdeja A . Fully 2'-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J Med Chem. 2005; 48(4):901-4. DOI: 10.1021/jm049167j. View

Das R, Laederach A, Pearlman S, Herschlag D, Altman R . SAFA: semi-automated footprinting analysis software for high-throughput quantification of nucleic acid footprinting experiments. RNA. 2005; 11(3):344-54. PMC: 1262685. DOI: 10.1261/rna.7214405. View

Millevoi S, Moine H, Vagner S . G-quadruplexes in RNA biology. Wiley Interdiscip Rev RNA. 2012; 3(4):495-507. DOI: 10.1002/wrna.1113. View

Datta B, Armitage B . Hybridization of PNA to structured DNA targets: quadruplex invasion and the overhang effect. J Am Chem Soc. 2001; 123(39):9612-9. DOI: 10.1021/ja016204c. View

10.

Todd A, Johnston M, Neidle S . Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res. 2005; 33(9):2901-7. PMC: 1140077. DOI: 10.1093/nar/gki553. View

11.

Hagihara M, Yamauchi L, Seo A, Yoneda K, Senda M, Nakatani K . Antisense-induced guanine quadruplexes inhibit reverse transcription by HIV-1 reverse transcriptase. J Am Chem Soc. 2010; 132(32):11171-8. DOI: 10.1021/ja1032088. View

12.

Sundquist W, Klug A . Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature. 1989; 342(6251):825-9. DOI: 10.1038/342825a0. View

13.

Green J, Ying L, Klenerman D, Balasubramanian S . Kinetics of unfolding the human telomeric DNA quadruplex using a PNA trap. J Am Chem Soc. 2003; 125(13):3763-7. DOI: 10.1021/ja029149w. View

14.

Postberg J, Tsytlonok M, Sparvoli D, Rhodes D, Lipps H . A telomerase-associated RecQ protein-like helicase resolves telomeric G-quadruplex structures during replication. Gene. 2012; 497(2):147-54. PMC: 3650557. DOI: 10.1016/j.gene.2012.01.068. View

15.

Sporn J, Kustatscher G, Hothorn T, Collado M, Serrano M, Muley T . Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene. 2009; 28(38):3423-8. DOI: 10.1038/onc.2009.26. View

16.

Di Giammartino D, Nishida K, Manley J . Mechanisms and consequences of alternative polyadenylation. Mol Cell. 2011; 43(6):853-66. PMC: 3194005. DOI: 10.1016/j.molcel.2011.08.017. View

17.

Huppert J . Four-stranded nucleic acids: structure, function and targeting of G-quadruplexes. Chem Soc Rev. 2008; 37(7):1375-84. DOI: 10.1039/b702491f. View

18.

Panyutin I, Onyshchenko M, Englund E, Appella D, Neumann R . Targeting DNA G-quadruplex structures with peptide nucleic acids. Curr Pharm Des. 2012; 18(14):1984-91. PMC: 3523305. DOI: 10.2174/138161212799958440. View

19.

Brosseau J, Lucier J, Lapointe E, Durand M, Gendron D, Gervais-Bird J . High-throughput quantification of splicing isoforms. RNA. 2009; 16(2):442-9. PMC: 2811672. DOI: 10.1261/rna.1877010. View

20.

Lorenz R, Bernhart S, Honer Zu Siederdissen C, Tafer H, Flamm C, Stadler P . ViennaRNA Package 2.0. Algorithms Mol Biol. 2011; 6:26. PMC: 3319429. DOI: 10.1186/1748-7188-6-26. View