Difference: RodriguezCai07 (6 vs. 7)

Revision 712 Apr 2007 - Main.JasperShahn

 
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Rodriguez FA, Cai Y, Lin C, Tang Y, Kolbanovskiy A, Amin S, Patel DJ, Broyde S, ... 'Exocyclic amino groups of flanking guanines govern sequence-dependent adduct conformations and local structural distortions for minor groove-aligned benzo[a]pyrenyl-guanine lesions in a GG mutation hotspot context.' Nucleic Acids Res 2007 in press nyu.gif mskc.gif
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Rodriguez FA, Cai Y, Lin C, Tang Y, Kolbanovskiy A, Amin S, Patel DJ, Broyde S, ... 'Exocyclic amino groups of flanking guanines govern sequence-dependent adduct conformations and local structural distortions for minor groove-aligned benzo[a]pyrenyl-guanine lesions in a GG mutation hotspot context.' Nucleic Acids Res 35 1555–1568 nyu.gif mskc.gif
  The environmental carcinogen benzo[a]pyrene (BP) is metabolized to reactive diol epoxides that bind to cellular DNA by predominantly forming N2-guanine adducts (G*). Mutation hotspots for these adducts are frequently found in 5'- ...GG... dinucleotide sequences, but their origins are poorly understood. Here we used high resolution NMR and molecular dynamics simulations to investigate differences in G* adduct conformations in 5'- ...CG*GC... and 5'-...CGG*C... sequence contexts in otherwise identical 12-mer duplexes. The BP rings are positioned 50 along the modified strand in the minor groove in both cases. However, subtle orientational differences cause strong distinctions in structural distortions of the DNA duplexes, because the exocyclic amino groups of flanking guanines on both strands compete for space with the BP rings in the minor groove, acting as guideposts for placement of the BP. In the 50- ... CGG*C... case, the 50-flanking G!C base pair is severely untwisted, concomitant with a bend deduced from electrophoretic mobility. In the 50- ...CG*GC... context, there is no untwisting, but there is significant destabilization of the 50-flanking Watson–Crick base pair. The minor groove width opens near the lesion in both cases, but more for 50- ...CGG*C.... Differential sequence-dependent removal rates of this lesion result and may contribute to the mutation hotspot phenomenon.
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