title: Structure-specific recognition of Friedreich's ataxia (GAA)n repeats by benzoquinoquinoxaline derivatives.
abstract: Expansion of GAA triplet repeats in intron 1 of the FXN gene reduces frataxin expression and causes Friedreich's ataxia. (GAA)n repeats form non-B-DNA structures, including triple helix H-DNA and higher-order structures (sticky DNA). In the proposed mechanisms of frataxin gene silencing, central unanswered questions involve the characterization of non-B-DNA structure(s) that are strongly suggested to play a role in frataxin expression. Here we examined (GAA)n binding by triplex-stabilizing benzoquinoquinoxaline (BQQ) and the corresponding triplex-DNA-cleaving BQQ-1,10-phenanthroline (BQQ-OP) compounds. We also examined the ability of these compounds to act as structural probes for H-DNA formation within higher-order structures at pathological frataxin sequences in plasmids. DNA-complex-formation analyses with a gel-mobility-shift assay and sequence-specific probing of H-DNA-forming (GAA)n sequences by single-strand oligonucleotides and triplex-directed cleavage demonstrated that a parallel pyrimidine (rather than purine) triplex is the more stable motif formed at (GAA)n repeats under physiologically relevant conditions.
authors.affiliation: Department of Molecular Biology and Functional Genomics, Stockholm University, Svante Arrhenius väg 20C, 10691 Stockholm, Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Bergquist
authors.forename: Abbas
authors.initials: A
authors.lastname: Nikravesh
authors.forename: Raquel Domingo
authors.initials: RD
authors.lastname: Fernández
authors.forename: Veronica
authors.initials: V
authors.lastname: Larsson
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Nguyen
authors.forename: Liam
authors.initials: L
authors.lastname: Good
authors.forename: Rula
authors.initials: R
authors.lastname: Zain
mesh_terms: D004247:DNA / Q000737:chemistry*; D005621:Friedreich Ataxia / Q000378:metabolism*; D006801:Humans; D009690:Nucleic Acid Conformation; D010957:Plasmids; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011810:Quinoxalines; C032931:benzoquinoxaline; D004247:DNA