Energy crosstalk between DNA lesions: implications for allosteric coupling of DNA repair and triplet repeat expansion pathways

Abstract

Energy coupling between distal DNA domains may have profound regulatory consequences for biological processes, allowing for allosteric control of nucleic acid function. Repair of oxidative lesions at or near triplet repeat domains can enhance DNA expansion events that result in debilitating disease states. We report here position, distance, and lesion-dependent energy crosstalk between pairs of lesions in a triplet repeat bulge loop and an adjacent duplex domain. We discuss the implications of such coupled communication between lesions in distal loop and duplex domains for lesion repair and DNA expansion associated with diseases.

Figure 1

Experimentally measured excess heat capacity curves for lesion pairs O(n)-O (Fig 1A), O(n)-F (Fig 1B), F(n)-O (Fig 1C), and F(n)-F (Fig 1D) (n=1,3, or 5). X(1)-X lesion pairs are shown in red; X(3)-X lesion pairs are shown in green; and X(5)-X lesion pairs are shown in blue; For comparison, shown in black are the excess heat capacity curves for the Ω-DNA constructs with the corresponding single lesion in the downstream domain only.

Figure 2

Comparison of the different Ω_DNA families. The difference in low temperature fitted enthalpy (ΔH_(fit,1)) relative to ΔH_(fit,1) of the unmodified parent Ω-DNA is shown.

SCHEME 1

We refer to the bulge loop construct shown in Scheme 1 as an Ω-DNA based on its similarity to the Greek letter Ω when represented in two dimensions. We will adhere to the following nomenclature based on lesion type and position listed in the following order: identity of lesion in bulge loop; followed by a number in parenthesis of the CAG repeat containing the lesion; followed by the identity of the fixed position lesion in the downstream domain. Thus, O(3)-F refers to the member of the O(n)-F family of Ω-DNA constructs that contains the 8oxoG lesion in the 3^rd CAG repeat and the F lesion in the downstream duplex domain. The designation (n) in place of a specific number within the parenthesis denotes the entire family of DNA lesion pairs; thus, O(n)-F refers to the three Ω-DNA constructs in which n=1, n=2, and n=5.