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.