Journal
CHEMBIOCHEM
Volume 12, Issue 15, Pages 2365-2374Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201100354
Keywords
antiparallel triplex; G-quadruplexes; intercalations; TINA; triple helical DNA
Funding
- French Ministry of Foreign Affairs
- New Zealand Ministry of Research, Science and Technology
- Dumont d'Urville [18961YF]
- Marsden grant [MAU0704]
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The majority of studies on DNA triple helices have been focused on pH-sensitive parallel triplexes with Hoogsteen CTcontaining third strands that require protonation of cytosines. Reverse Hoogsteen GT/GA-containing antiparallel triplex-forming oligonucleotides (TFOs) do not require an acidic pH but their applicability in triplex technology is limited because of their tendency to form undesired highly stable aggregates such as G-quadruplexes. In this study, G-rich oligonucleotides containing 2-4 insertions of twisted intercalating nucleic acid (TINA) monomers are demonstrated to disrupt the formation of G-quadruplexes and form stable antiparallel triplexes with target DNA duplexes. The structure of TINA-incorporated oligo-nucleotides was optimized, the rules of their design were established and the optimal triplex-forming oligonucleotides were selected. These oligonucleotides show high affinity towards a 16 bp homopurine model sequence from the HIV-1 genome; dissociation constants as low as 160 nm are observed whereas the unmodified TFO does not show any triplex formation and instead forms an intermolecular G-quadruplex with T-m exceeding 90 degrees C in the presence of 50 mm NaCl. Here we present a set of rules that help to reach the full potential of TINA-TFOs and demonstrate the effect of TINA on the formation and stability of triple helical DNA.
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