Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts

Shixiang Yan, Min Wu, Tonko Buterin, Hanspeter Naegeli, Nicholas E. Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

We investigate the influence of base sequence context on the conformations of the 10S (+)-and 10R (-)-trans-anti-[BP]-N 6-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA *A sequence context, and here we report results for the CA *C sequence. Our simulations indicate that the base sequence context affects the syn-anti conformational equilibrium in the 10S (+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA *C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S (+) adduct for the CA *C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S (+) adduct, has been found in our simulations for the CA *C sequence, which could account for the enhanced nucleotide excision repair as well as the syn-anti equilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.

Original languageEnglish (US)
Pages (from-to)2339-2354
Number of pages16
JournalBiochemistry
Volume42
Issue number8
DOIs
StatePublished - Mar 4 2003

Fingerprint

Benzo(a)pyrene
Epoxy Compounds
Adenine
DNA Repair
Repair
Nucleotides
Assays
Molecular Dynamics Simulation
Cell Extracts
Hydrogen
Interfacial energy
Isomers
Free energy
Conformations
Molecular dynamics
Hydrogen bonds
Cells
Computer simulation
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts. / Yan, Shixiang; Wu, Min; Buterin, Tonko; Naegeli, Hanspeter; Geacintov, Nicholas E.; Broyde, Suse.

In: Biochemistry, Vol. 42, No. 8, 04.03.2003, p. 2339-2354.

Research output: Contribution to journalArticle

@article{94e63a17e2b646d5b791c35718d1f310,
title = "Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts",
abstract = "We investigate the influence of base sequence context on the conformations of the 10S (+)-and 10R (-)-trans-anti-[BP]-N 6-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA *A sequence context, and here we report results for the CA *C sequence. Our simulations indicate that the base sequence context affects the syn-anti conformational equilibrium in the 10S (+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA *C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S (+) adduct for the CA *C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S (+) adduct, has been found in our simulations for the CA *C sequence, which could account for the enhanced nucleotide excision repair as well as the syn-anti equilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.",
author = "Shixiang Yan and Min Wu and Tonko Buterin and Hanspeter Naegeli and Geacintov, {Nicholas E.} and Suse Broyde",
year = "2003",
month = "3",
day = "4",
doi = "10.1021/bi0270081",
language = "English (US)",
volume = "42",
pages = "2339--2354",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Role of base sequence context in conformational equilibria and nucleotide excision repair of benzo[a]pyrene diol epoxide-adenine adducts

AU - Yan, Shixiang

AU - Wu, Min

AU - Buterin, Tonko

AU - Naegeli, Hanspeter

AU - Geacintov, Nicholas E.

AU - Broyde, Suse

PY - 2003/3/4

Y1 - 2003/3/4

N2 - We investigate the influence of base sequence context on the conformations of the 10S (+)-and 10R (-)-trans-anti-[BP]-N 6-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA *A sequence context, and here we report results for the CA *C sequence. Our simulations indicate that the base sequence context affects the syn-anti conformational equilibrium in the 10S (+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA *C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S (+) adduct for the CA *C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S (+) adduct, has been found in our simulations for the CA *C sequence, which could account for the enhanced nucleotide excision repair as well as the syn-anti equilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.

AB - We investigate the influence of base sequence context on the conformations of the 10S (+)-and 10R (-)-trans-anti-[BP]-N 6-dA adducts through molecular dynamics (MD) simulations with free energy calculations, and relate the structural findings to results of nucleotide excision repair (NER) assays in human cell extracts. In previous studies, these adducts were studied in the CA *A sequence context, and here we report results for the CA *C sequence. Our simulations indicate that the base sequence context affects the syn-anti conformational equilibrium in the 10S (+) adduct by modulating the barrier heights between these states on the energy surface, with a higher barrier in the CA *C case. Our nucleotide excision repair assay finds greater NER susceptibilities in the 10S (+) adduct for the CA *C sequence context. A structural rationale ties together these results. A sequence specific hydrogen bond, accompanied by a significantly increased roll and consequent bending in the 10S (+) adduct, has been found in our simulations for the CA *C sequence, which could account for the enhanced nucleotide excision repair as well as the syn-anti equilibrium difference we observe in this isomer and sequence. Such sequence specific differential repair could contribute to the existence of mutational hotspots and thereby contribute to the complexity of cancer initiation.

UR - http://www.scopus.com/inward/record.url?scp=0037418535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037418535&partnerID=8YFLogxK

U2 - 10.1021/bi0270081

DO - 10.1021/bi0270081

M3 - Article

VL - 42

SP - 2339

EP - 2354

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 8

ER -