Structure and mechanism of formation of the H-y5 isomer of an intramolecular DNA triple helix

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Abstract

H-DNA, thought to play a regulatory role in transcription, exists in two isomeric forms, H-y3 and H-y5. We present the first solution structure of a DNA fragment representing the H-y5 fold. The structure shows the H-y5 triple helix, and for the first time how in an H-DNA isomer the purine strand extension interacts with the triplex loop. It gives direct insight into the mechanism of H-DNA formation, and explains a host of biochemical and biophysical data on the relative stability of the H-DNA isomers. In addition, the observed interaction of the purine strand extension and the triplex loop provides new clues to the design of clamp-type triple helix-forming oligonucleotides.

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Figure 1: Schematic representation of the transition of a, the double helix into b, the two possible isomers of H-DNA.
Figure 2: a, b, Sequential NOE interactions in the triplex loop and the 3′ tail of H-y5 shown in expanded regions of the 80 ms 750 MHz NOESY spectrum.
Figure 3: The solution structure of the H-y5 DNA fragment.
Figure 4: a, Haasnoot plot30,31 for a triplex loop.

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Acknowledgements

NMR spectra were recorded at the SON National hf-NMR Facility and the NMR large-scale facility (Nijmegen/Utrecht, The Netherlands). We thank J.J.M. Joordens for technical assistance and R.A.M. Avontuur for his contribution in the optimization routines for the P.E.COSY and NOESY based methods in the sugar pucker analysis. G. Martinez and J. Hof are thanked for critical reading of the manuscript, and M. Nilges for valuable help on the implementation of the torsion angle dynamics.

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Correspondence to Sybren S. Wijmenga.

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