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

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,...

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Main Authors: Jens Völker, G. Eric Plum, Vera Gindikin, Kenneth J. Breslauer
Format: Article
Language:English
Published: MDPI AG 2019-11-01
Series:Biomolecules
Subjects:
Online Access:https://www.mdpi.com/2218-273X/9/11/709
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spelling doaj-60573dfbe26541619e406cc650705f7a2020-11-25T02:23:07ZengMDPI AGBiomolecules2218-273X2019-11-0191170910.3390/biom9110709biom9110709Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA RepairJens Völker0G. Eric Plum1Vera Gindikin2Kenneth J. Breslauer3Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USAIBET Inc, Columbus, OH 43220, USADepartment of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USADepartment of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USADNA 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.https://www.mdpi.com/2218-273X/9/11/709dna energy landscapesdifferential scanning calorimetry (dsc)dynamic dna statestriplet repeat expansion (tre)abasic site lesion8oxog lesionbase excision repair (ber)
collection DOAJ
language English
format Article
sources DOAJ
author Jens Völker
G. Eric Plum
Vera Gindikin
Kenneth J. Breslauer
spellingShingle Jens Völker
G. Eric Plum
Vera Gindikin
Kenneth J. Breslauer
Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
Biomolecules
dna energy landscapes
differential scanning calorimetry (dsc)
dynamic dna states
triplet repeat expansion (tre)
abasic site lesion
8oxog lesion
base excision repair (ber)
author_facet Jens Völker
G. Eric Plum
Vera Gindikin
Kenneth J. Breslauer
author_sort Jens Völker
title Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
title_short Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
title_full Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
title_fullStr Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
title_full_unstemmed Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
title_sort dynamic dna energy landscapes and substrate complexity in triplet repeat expansion and dna repair
publisher MDPI AG
series Biomolecules
issn 2218-273X
publishDate 2019-11-01
description 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.
topic dna energy landscapes
differential scanning calorimetry (dsc)
dynamic dna states
triplet repeat expansion (tre)
abasic site lesion
8oxog lesion
base excision repair (ber)
url https://www.mdpi.com/2218-273X/9/11/709
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