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Energy landscapes of dynamic ensembles of rolling triplet repeat bulge loops: implications for DNA expansion associated with disease states.

Völker J, Gindikin V, Klump HH, Plum GE, Breslauer KJ - J. Am. Chem. Soc. (2012)

Bottom Line: In the aggregate, our data reveal that dynamic ensembles within repeat domains profoundly impact the overall energetics of such DNA constructs as well as the distribution of states by which they denature/renature.These static and dynamic influences within triplet repeat domains expand the conformational space available for selection and targeting by the DNA processing machinery.We propose that such dynamic ensembles and their associated impact on DNA properties influence pathways that lead to DNA expansion.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, USA.

ABSTRACT
DNA repeat domains can form ensembles of canonical and noncanonical states, including stable and metastable DNA secondary structures. Such sequence-induced structural diversity creates complex conformational landscapes for DNA processing pathways, including those triplet expansion events that accompany replication, recombination, and/or repair. Here we demonstrate further levels of conformational complexity within repeat domains. Specifically, we show that bulge loop structures within an extended repeat domain can form dynamic ensembles containing a distribution of loop positions, thereby yielding families of positional loop isomers, which we designate as "rollamers". Our fluorescence, absorbance, and calorimetric data are consistent with loop migration/translocation between sites within the repeat domain ("rollamerization"). We demonstrate that such "rollameric" migration of bulge loops within repeat sequences can invade and disrupt previously formed base-paired domains via an isoenthalpic, entropy-driven process. We further demonstrate that destabilizing abasic lesions alter the loop distributions so as to favor "rollamers" with the lesion positioned at the duplex/loop junction, sites where the flexibility of the abasic "universal hinge" relaxes unfavorable interactions and/or facilitates topological accommodation. Another strategic siting of an abasic site induces directed loop migration toward denaturing domains, a phenomenon that merges destabilizing domains. In the aggregate, our data reveal that dynamic ensembles within repeat domains profoundly impact the overall energetics of such DNA constructs as well as the distribution of states by which they denature/renature. These static and dynamic influences within triplet repeat domains expand the conformational space available for selection and targeting by the DNA processing machinery. We propose that such dynamic ensembles and their associated impact on DNA properties influence pathways that lead to DNA expansion.

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Schematic Representation of the All-TRepeat Loop Constructs “Frozen”in Fixed Positions: Placement of the Base-Paired CAG/CTG Domain, Indicatedby Red Letters, “Freezes” the All-T Loop Relative tothe Upstream and/or Downstream Nonrepetitive 11-mer Arms
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sch3: Schematic Representation of the All-TRepeat Loop Constructs “Frozen”in Fixed Positions: Placement of the Base-Paired CAG/CTG Domain, Indicatedby Red Letters, “Freezes” the All-T Loop Relative tothe Upstream and/or Downstream Nonrepetitive 11-mer Arms


Energy landscapes of dynamic ensembles of rolling triplet repeat bulge loops: implications for DNA expansion associated with disease states.

Völker J, Gindikin V, Klump HH, Plum GE, Breslauer KJ - J. Am. Chem. Soc. (2012)

Schematic Representation of the All-TRepeat Loop Constructs “Frozen”in Fixed Positions: Placement of the Base-Paired CAG/CTG Domain, Indicatedby Red Letters, “Freezes” the All-T Loop Relative tothe Upstream and/or Downstream Nonrepetitive 11-mer Arms
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3318849&req=5

sch3: Schematic Representation of the All-TRepeat Loop Constructs “Frozen”in Fixed Positions: Placement of the Base-Paired CAG/CTG Domain, Indicatedby Red Letters, “Freezes” the All-T Loop Relative tothe Upstream and/or Downstream Nonrepetitive 11-mer Arms
Bottom Line: In the aggregate, our data reveal that dynamic ensembles within repeat domains profoundly impact the overall energetics of such DNA constructs as well as the distribution of states by which they denature/renature.These static and dynamic influences within triplet repeat domains expand the conformational space available for selection and targeting by the DNA processing machinery.We propose that such dynamic ensembles and their associated impact on DNA properties influence pathways that lead to DNA expansion.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, USA.

ABSTRACT
DNA repeat domains can form ensembles of canonical and noncanonical states, including stable and metastable DNA secondary structures. Such sequence-induced structural diversity creates complex conformational landscapes for DNA processing pathways, including those triplet expansion events that accompany replication, recombination, and/or repair. Here we demonstrate further levels of conformational complexity within repeat domains. Specifically, we show that bulge loop structures within an extended repeat domain can form dynamic ensembles containing a distribution of loop positions, thereby yielding families of positional loop isomers, which we designate as "rollamers". Our fluorescence, absorbance, and calorimetric data are consistent with loop migration/translocation between sites within the repeat domain ("rollamerization"). We demonstrate that such "rollameric" migration of bulge loops within repeat sequences can invade and disrupt previously formed base-paired domains via an isoenthalpic, entropy-driven process. We further demonstrate that destabilizing abasic lesions alter the loop distributions so as to favor "rollamers" with the lesion positioned at the duplex/loop junction, sites where the flexibility of the abasic "universal hinge" relaxes unfavorable interactions and/or facilitates topological accommodation. Another strategic siting of an abasic site induces directed loop migration toward denaturing domains, a phenomenon that merges destabilizing domains. In the aggregate, our data reveal that dynamic ensembles within repeat domains profoundly impact the overall energetics of such DNA constructs as well as the distribution of states by which they denature/renature. These static and dynamic influences within triplet repeat domains expand the conformational space available for selection and targeting by the DNA processing machinery. We propose that such dynamic ensembles and their associated impact on DNA properties influence pathways that lead to DNA expansion.

Show MeSH
Related in: MedlinePlus