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Open AccessArticle

Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair

1
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
2
IBET Inc, Columbus, OH 43220, USA
3
The Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(11), 709; https://doi.org/10.3390/biom9110709
Received: 2 October 2019 / Revised: 29 October 2019 / Accepted: 31 October 2019 / Published: 6 November 2019
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
DNA repeat domains implicated in DNA expansion diseases exhibit complex conformational and energy landscapes that impact biological outcomes. These landscapes include ensembles of entropically driven positional interchanges between isoenergetic, isomeric looped states referred to as rollamers. Here, we present evidence for the position-dependent impact on repeat DNA energy landscapes of an oxidative lesion (8oxodG) and of an abasic site analogue (tetrahydrofuran, F), the universal intermediate in base excision repair (BER). We demonstrate that these lesions modulate repeat bulge loop distributions within the wider dynamic rollamer triplet repeat landscapes. We showed that the presence of a lesion disrupts the energy degeneracy of the rollameric positional isomers. This lesion-induced disruption leads to the redistribution of loop isomers within the repeat loop rollamer ensemble, favoring those rollameric isomers where the lesion is positioned to be energetically least disruptive. These dynamic ensembles create a highly complex energy/conformational landscape of potential BER enzyme substrates to select for processing or to inhibit processing. We discuss the implications of such lesion-induced alterations in repeat DNA energy landscapes in the context of potential BER repair outcomes, thereby providing a biophysical basis for the intriguing in vivo observation of a linkage between pathogenic triplet repeat expansion and DNA repair.
Keywords: DNA energy landscapes; differential scanning calorimetry (DSC); dynamic DNA states; triplet repeat expansion (TRE); abasic site lesion; 8oxoG lesion; base excision repair (BER) DNA energy landscapes; differential scanning calorimetry (DSC); dynamic DNA states; triplet repeat expansion (TRE); abasic site lesion; 8oxoG lesion; base excision repair (BER)
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MDPI and ACS Style

Völker, J.; Plum, G.E.; Gindikin, V.; Breslauer, K.J. Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair. Biomolecules 2019, 9, 709.

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