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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2019-11-01
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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 |
work_keys_str_mv |
AT jensvolker dynamicdnaenergylandscapesandsubstratecomplexityintripletrepeatexpansionanddnarepair AT gericplum dynamicdnaenergylandscapesandsubstratecomplexityintripletrepeatexpansionanddnarepair AT veragindikin dynamicdnaenergylandscapesandsubstratecomplexityintripletrepeatexpansionanddnarepair AT kennethjbreslauer dynamicdnaenergylandscapesandsubstratecomplexityintripletrepeatexpansionanddnarepair |
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