Nucleic Acids Research Advance Access originally published online on February 7, 2007
Nucleic Acids Research 2007 35(5):1555-1568; doi:10.1093/nar/gkm022
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Nucleic Acids Research, 2007, Vol. 35, No. 5 1555-1568
© 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
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
1Department of Chemistry and 2Biology, New York University, New York, NY, USA, 3Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA and 4Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
*To whom correspondence should be addressed. Tel: +1 212 998 8407; Fax: +1 212 998 8421; Email: ng1{at}nyu.edu
Received November 28, 2006. Revised December 29, 2006. Accepted January 2, 2007.
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.