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.

Abstract:

: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 5' 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 5'- ... CGG* C ... case, the 5'-flanking G . C base pair is severely untwisted, concomitant with a bend deduced from electrophoretic mobility. In the 5'- ... CG*GC ... context, there is no untwisting, but there is significant destabilization of the 5'-flanking Watson-Crick base pair. The minor groove width opens near the lesion in both cases, but more for 5'- ... CGG*C.... Differential sequence-dependent removal rates of this lesion result and may contribute to the mutation hotspot phenomenon.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Rodríguez FA,Cai Y,Lin C,Tang Y,Kolbanovskiy A,Amin S,Patel DJ,Broyde S,Geacintov NE

doi

10.1093/nar/gkm022

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

1555-68

issue

5

eissn

0305-1048

issn

1362-4962

pii

gkm022

journal_volume

35

pub_type

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