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DNA Mismatch-Specific Base Flipping by a Bisacridine Macrocycle

MPG-Autoren

Bleimling,  Nathalie
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98737

Weinhold,  Elmar
Abt. III: Physikalische Biochemie, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Zitation

David, A., Bleimling, N., Beuck, C., Lehn, J.-M., Weinhold, E., & Teulade-Fichou, M.-P. (2003). DNA Mismatch-Specific Base Flipping by a Bisacridine Macrocycle. ChemBioChem, 4(12): 1, pp. 1326-1331. Retrieved from http://dx.doi.org/10.1002/cbic.200300693.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0014-0C2C-9
Zusammenfassung
Most, if not all, enzymes that chemically modify nucleobases in DNA flip their target base from the inside of the double helix into an extrahelical position. This energetically unfavorable conformation is partly stabilized by specific binding of the apparent abasic site being formed. Thus, DNA base-flipping enzymes, like DNA methyltransferases and DNA glycosylases, generally bind very strongly to DNA containing abasic sites or abasic-site analogues. The macrocyclic bisacridine BisA has previously been shown to bind abasic sites. Herein we demonstrate that it is able to specifically recognize DNA base mismatches and most likely induces base flipping. Specific binding of BisA to DNA mismatches was studied by thermal denaturation experiments by using short duplex oligodeoxynucleotides containing central TT, TC, or TG mismatches or a TA match. In the presence of the macrocycle a strong increase in the melting temperature of up to 7.1 °C was observed for the mismatch-containing duplexes, whereas the melting temperature of the fully matched duplex was unaffected. Furthermore, BisA binding induced an enhanced reactivity of the mispaired thymine residue in the DNA toward potassium permanganate oxidation. A comparable reactivity has previously been observed for a TT target base mismatch in the presence of DNA methyltransferase MTaqI. This similarity to a known base-flipping enzyme suggests that insertion of BisA into the DNA helix displaces the mispaired thymine residue into an extrahelical position, where it should be more prone to chemical oxidation. Thus, DNA base flipping does not appear to be limited to DNA-modifying enzymes but it is likely to also be induced by a small synthetic molecule binding to a thermodynamically weakened site in DNA.