DNA repair and DNA triplet repeat expansion: the impact of abasic lesions on triplet repeat DNA energetics.
Enhanced levels of DNA triplet expansion are observed when base excision repair (BER) of oxidative DNA base damage (e.g., 8-oxo-dG) occurs at or near CAG repeat sequences. This observation suggests an interplay between processing mechanisms required for DNA repair and expansion pathways that yield genotypes associated with many neurological/developmental disorders. It has been proposed that DNA expansion involves the transient formation within the triplet repeat domains of non-native slipped DNA structures that are incorrectly processed by the BER machinery of repair during DNA synthesis. We show here that replacement within a triplet repeat bulge loop domain of a guanosine residue by an abasic site, the universal BER intermediate, increases the population of slipped/looped DNA structures relative to the corresponding lesion-free construct. Such abasic lesion-induced energetic enhancement of slipped/looped structures provides a linkage between BER and DNA expansion. We discuss how the BER machinery of repair may be influenced by abasic-induced energetic alterations in the properties of regions proximal to and/or within triplet repeat domains, thereby potentially modulating levels of DNA expansion.
Völker
Jens
J
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, USA.
Plum
G Eric
GE
Klump
Horst H
HH
Breslauer
Kenneth J
KJ
D004247:DNA / Q000737:chemistry*; D004260:DNA Repair; D006151:Guanosine / Q000737:chemistry*; D006358:Hot Temperature; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D013816:Thermodynamics; D019680:Trinucleotide Repeat Expansion
D006151:Guanosine; D004247:DNA