Völker J., Plum G.E., Klump H.H., Breslauer K.J.
Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854, United States; IBET Inc., 1507 Chambers Road, Columbus, OH 43212, United States; Department of Molecular and Cell Biology, University of Cape Town, Private Bag, Rondebosch 7800, South Africa; Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
Völker, J., Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854, United States; Plum, G.E., Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854, United States, IBET Inc., 1507 Chambers Road, Columbus, OH 43212, United States; Klump, H.H., Department of Molecular and Cell Biology, University of Cape Town, Private Bag, Rondebosch 7800, South Africa; Breslauer, K.J., Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854, United States, Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
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. © 2009 American Chemical Society.
Base excision repairs; DNA repair; DNA structure; DNA synthesis; Guanosine; Looped structures; Non-native; Transient formation; DNA; Expansion; Genes; Machinery; Nucleic acids; Repair; Synthesis (chemical); DNA sequences; DNA base; guanosine; repetitive DNA; tetrahydrofuran; article; DNA damage; DNA repair; DNA structure; DNA synthesis; energy transfer; excision repair; molecular dynamics; DNA; DNA Repair; Guanosine; Hot Temperature; Nucleic Acid Conformation; Nucleic Acid Denaturation; Thermodynamics; Trinucleotide Repeat Expansion