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Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden..
Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden..
KTH Royal Inst Technol, Sch Chem Sci & Engn, Dept Chem, Stockholm, Sweden.;Fdn IMDEA Nanociencia, 9 Campus Univ Cantoblanco, Madrid, Spain..
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0165788Article in journal (Refereed) Published
Abstract [en]

Expansion of (GAA)(n) repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)(n) expansions form non-canonical structures, including intramolecular triplex (H-DNA), and Rloops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)(n) expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)(n) repeats of different lengths (short: n= 9, medium: n= 75 or long: n= 115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA) 4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT) 5-PNA did not. We present evidence that (GAA) 4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT) 5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.

Place, publisher, year, edition, pages
2016. Vol. 11, no 11, article id e0165788
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-312088DOI: 10.1371/journal.pone.0165788ISI: 000387794600020OAI: oai:DiVA.org:uu-312088DiVA, id: diva2:1071236
Available from: 2017-02-03 Created: 2017-01-04 Last updated: 2017-11-29Bibliographically approved

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