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.
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.
Rodríguez
Fabián A
FA
Department of Chemistry, New York University, New York, NY, USA.
Cai
Yuqin
Y
Lin
Chin
C
Tang
Yijin
Y
Kolbanovskiy
Alexander
A
Amin
Shantu
S
Patel
Dinshaw J
DJ
Broyde
Suse
S
Geacintov
Nicholas E
NE
D000588:Amines / Q000737:chemistry; D001483:Base Sequence; D001580:Benzopyrenes / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006147:Guanine / Q000737:chemistry*; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D011522:Protons; D013696:Temperature
D000588:Amines; D001580:Benzopyrenes; D018736:DNA Adducts; D011522:Protons; C478198:benzo(a)pyrene N2-dG adduct; D006147:Guanine; D003849:Deoxyguanosine