The binding of the Co(II) complex of dimeric chromomycin A3 to GC sites with flanking G:G mismatches

Some neurological diseases are correlated with expansion of (CXG)n trinucleotide repeats, which contain many contiguous GpC flanked by mismatched X/X base pair. This study focused on the binding of the Co(II) complex of dimeric chromomycin A3(Chro), CoII(Chro)2, to DNA with CXG trinucleotide repeats. The present study showed that GC sites with flanking G:G mismatches provide an excellent binding site for CoII(Chro)2 as shown by surface plasmon resonance and fluorescence analysis, compared to GC sites with flanking A:A, T:T, or C:C mismatches. In addition, we measured the ability of CoII(Chro)2 to act on the hairpin DNA of (CGG)16. We observed that CoII(Chro)2 could stabilize and trap the cruciform conformation of (CGG)16. Furthermore, two CoII(Chro)2 molecules may bind at the two GpC sites separated by at least one GC site in the hairpin structure of (CGG)16. In a synthetic self-priming DNA model, 5′-(CGG)16(CCG)6-3′, CoII(Chro)2 can interfere with the expansion process of CGG triplet repeats, as shown by a gel electrophoretic expansion assay. Here, we first report the acting of CoII(Chro)2, the groove-binding drug, to trinucleotide repeats. Our results provide the possible biological consequence of CoII(Chro)2 bound to CGG triplet repeat sequences.

An illustration to explain how DNA synthesis is interrupted by CoII(chromomycin A3)2-stabilized hairpin structures in CGG repeats is shown.Figure optionsDownload as PowerPoint slideHighlights
► Chromomycin A3 form a dimer complex coordinated with Co(II)
► GC sites with flanking G:G mismatches provide an excellent binding site for CoII(chromomycin A3)2.
► CoII(chromomycin A3)2 could stabilize and trap the cruciform conformation of (CGG)16.
► CoII(chromomycin A3)2 can interfere with the expansion process of CGG triplet repeats.