Energetic Coupling Between Clustered Lesions Modulated by Intervening Triplet Repeat Bulge Loops: Allosteric Implications for DNA Repair and Triplet Repeat Expansion

Clusters of closely spaced oxidative DNA lesions present challenges to the cellular repair machinery. When located in opposing strands, base excision repair (BER) of such lesions can lead to double strand DNA breaks (DSB). Activation of BER and DSB repair pathways has been implicated in inducing enhanced expansion of triplet repeat sequences. We show here that energy coupling between distal lesions (8oxodG and/or abasic sites) in opposing DNA strands can be modulated by a triplet repeat bulge loop located between the lesion sites. We find this modulation to be dependent on the identity of the lesions (8oxodG vs. abasic site) and the positions of the lesions (upstream vs. downstream) relative to the intervening bulge loop domain. We discuss how such bulge loop-mediated lesion crosstalk might influence repair processes, while favoring DNA expansion, the genotype of triplet repeat diseases. (C) 2009 Wiley Periodicals, Inc. Blopolymers 93: 355-369, 2010.