title: Impact of bulge loop size on DNA triplet repeat domains: Implications for DNA repair and expansion.
abstract: Repetitive DNA sequences exhibit complex structural and energy landscapes, populated by metastable, noncanonical states, that favor expansion and deletion events correlated with disease phenotypes. To probe the origins of such genotype-phenotype linkages, we report the impact of sequence and repeat number on properties of (CNG) repeat bulge loops. We find the stability of duplexes with a repeat bulge loop is controlled by two opposing effects; a loop junction-dependent destabilization of the underlying double helix, and a self-structure dependent stabilization of the repeat bulge loop. For small bulge loops, destabilization of the underlying double helix overwhelms any favorable contribution from loop self-structure. As bulge loop size increases, the stabilizing loop structure contribution dominates. The role of sequence on repeat loop stability can be understood in terms of its impact on the opposing influences of junction formation and loop structure. The nature of the bulge loop affects the thermodynamics of these two contributions differently, resulting in unique differences in repeat size-dependent minima in the overall enthalpy, entropy, and free energy changes. Our results define factors that control repeat bulge loop formation; knowledge required to understand how this helix imperfection is linked to DNA expansion, deletion, and disease phenotypes.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Rd, Piscataway, NJ, 08854.
authors.forename: Jens
authors.initials: J
authors.lastname: Völker
authors.forename: G Eric
authors.initials: GE
authors.lastname: Plum
authors.forename: Vera
authors.initials: V
authors.lastname: Gindikin
authors.forename: Horst H
authors.initials: HH
authors.lastname: Klump
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Breslauer
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D009690:Nucleic Acid Conformation; D013816:Thermodynamics; D018911:Trinucleotide Repeats
chemical_list: D004247:DNA
keywords: DNA loop structure; DNA stability; DNA thermodynamics; calorimetry; circular dichroism (CD); trinucleotide-repeat diseases