Abstract
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.
Highlights
Sequence repeat DNA domains exhibit enhanced propensities to undergo expansion and deletion events in vivo, frequently with deleterious outcomes for the affected organism [1,2,3,4,5,6,7,8]
We have shown that a bulge loop structure comprised of a part of a larger repeat sequence domain can exist as several isoenergetic loop isomers called rollamers in dynamic equilibrium with each other [44]
We designed a family of rollamer constructs containing a (CAG)4 repeat bulge loop that can exist in three possible isoenergetic loop positions by combining a [CAG]6 oligonucleotide with a partially complementary [CTG]2 oligonucleotide, as per the rules we previously described [44]
Summary
Sequence repeat DNA domains exhibit enhanced propensities to undergo expansion and deletion events in vivo, frequently with deleterious outcomes for the affected organism [1,2,3,4,5,6,7,8]. The three isoenergetic local minima relative to the global minimum of the corresponding fully bonded duplex state reflect each of the three rollameric positional isomers shown schematically in the absence of a lesion, which creates substrate complexity for the processing of such rollamer domains. This degenerate distribution of isoenergetic rollameric states potentially provides an entropic explanation for the observed threshold phenomenon for DNA expansion [43,44]. Our results provide an intriguing biophysical basis for the in vivo observation of the coupling of DNA repair and DNA triplet repeat expansion
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