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

Fabián A. Rodríguez, Yuqin Cai, Chin Lin, Yijin Tang, Alexander Kolbanovskiy, Shantu Amin, Dinshaw J. Patel, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1555-1568
Number of pages14
JournalNucleic Acids Research
Volume35
Issue number5
DOIs
StatePublished - Mar 2007

Fingerprint

Guanine
Base Pairing
Environmental Carcinogens
Mutation
Benzo(a)pyrene
DNA
Epoxy Compounds
Molecular Dynamics Simulation

ASJC Scopus subject areas

  • Genetics

Cite this

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. / Rodríguez, Fabián A.; Cai, Yuqin; Lin, Chin; Tang, Yijin; Kolbanovskiy, Alexander; Amin, Shantu; Patel, Dinshaw J.; Broyde, Suse; Geacintov, Nicholas E.

In: Nucleic Acids Research, Vol. 35, No. 5, 03.2007, p. 1555-1568.

Research output: Contribution to journalArticle

@article{d8283010c778488cb9d420eb2969a904,
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.",
author = "Rodr{\'i}guez, {Fabi{\'a}n A.} and Yuqin Cai and Chin Lin and Yijin Tang and Alexander Kolbanovskiy and Shantu Amin and Patel, {Dinshaw J.} and Suse Broyde and Geacintov, {Nicholas E.}",
year = "2007",
month = "3",
doi = "10.1093/nar/gkm022",
language = "English (US)",
volume = "35",
pages = "1555--1568",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - 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

AU - Rodríguez, Fabián A.

AU - Cai, Yuqin

AU - Lin, Chin

AU - Tang, Yijin

AU - Kolbanovskiy, Alexander

AU - Amin, Shantu

AU - Patel, Dinshaw J.

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

PY - 2007/3

Y1 - 2007/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34247213435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247213435&partnerID=8YFLogxK

U2 - 10.1093/nar/gkm022

DO - 10.1093/nar/gkm022

M3 - Article

C2 - 17287290

AN - SCOPUS:34247213435

VL - 35

SP - 1555

EP - 1568

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 5

ER -