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 Journal Article
| Authors: | Rodríguez, F. A.; Cai, Y.; Lin, C.; Tang, Y.; Kolbanovskiy, A.; Amin, S.; Patel, D. J.; Broyde, S.; Geacintov, N. E. |
| Article Title: | 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′- ⋯ CGU*GC⋯ and 5′- ⋯ CGG*⋯ 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* ⋯ 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. © 2007 Oxford University Press. |
| Keywords: | gene mutation; sequence analysis; mutation; protein conformation; molecular dynamics; amines; double stranded dna; guanine; nucleotide sequence; nuclear magnetic resonance spectroscopy; base sequence; temperature; benzo[a]pyrene; deoxyguanosine; base pairing; dna adduct; dna flanking region; dna structure; dna adducts; models, molecular; protons; nucleic acid conformation; electrophoretic mobility; dna denaturation; dna conformation; nuclear magnetic resonance, biomolecular; benzopyrenes; dna strand; cytosine |
| Journal Title: | Nucleic Acids Research |
| Volume: | 35 |
| Issue: | 5 |
| ISSN: | 0305-1048 |
| Publisher: | Oxford University Press |
| Date Published: | 2007-03-01 |
| Start Page: | 1555 |
| End Page: | 1568 |
| Language: | English |
| DOI: | 10.1093/nar/gkm022 |
| PUBMED: | 17287290 |
| PROVIDER: | scopus |
| PMCID: | PMC1865068 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 17 November 2011" - "CODEN: NARHA" - "Source: Scopus" |
