Solution structure of a DNA duplex containing 8-hydroxy-2′-deoxyguanosine opposite deoxyguanosine

Varatharasa Thiviyanathan, Anoma Somasunderam, Tapas Hazra, Sankar Mitra, David G. Gorenstein

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Deoxyguanosine residues are hydroxylated by reactive oxygen species at the C-8 position to form 8-hydroxy-2′-deoxyguanosine (8-OG), one of the most important mutagenic lesions in DNA. Though the spontaneous G:C to C:G transversions are rare events, the pathways leading to this mutation are not established. An 8-OG:G mispair, if not corrected by DNA repair enzymes, could lead to G:C to C:G transversions. NMR spectroscopy and restrained molecular dynamics calculations are used to refine the solution structure of the base mismatch formed by the 8-OG:G pair on a self complementary DNA dodecamer duplex d(CGCGAATT8-O-GGCG)2. The results reveal that the 8-OG base is inserted into the helix) and forms Hoogsteen base-pairing with the G on the opposite strand. The 8-OG:G base-pairs are seen to be stabilized by two hydrogen bonding interactions, one between the H7 of the 8-OG and the O6 of the G, and a three-center hydrogen bonding between the O8 of the 8-OG and the imino and amino protons of the G. The 8-OG:G base-pairs are very well stacked between the Watson-Crick base-paired flanking bases. Both strands of the DNA duplex adopt right-handed conformations. All of the unmodified bases, including the G at the lesion site, adopt anti glycosidic torsion angles and form Watson-Crick base-pairs. At the lesion site, the 8-OG residues adopt syn conformations. The structural studies demonstrate that 8-OG(syn):G(anti) forms a stable pair in the interior of the duplex, providing a basis for the in vivo incorporation of G opposite 8-OG. Calculated helical parameters and backbone torsional angles, and the observed 31P chemical shifts, indicate that the structure of the duplex is perturbed near lesion sites, with the local unwinding of the double helix. The melting temperature of the 8-OG:G containing duplex is only 2.6 deg. C less than the tm of the unmodified duplex.

Original languageEnglish (US)
Pages (from-to)433-442
Number of pages10
JournalJournal of Molecular Biology
Volume325
Issue number3
DOIs
StatePublished - 2003

Fingerprint

Deoxyguanosine
DNA
Base Pairing
Hydrogen Bonding
8-oxo-7-hydrodeoxyguanosine
DNA Repair Enzymes
Molecular Dynamics Simulation
Freezing
Protons
Reactive Oxygen Species
Magnetic Resonance Spectroscopy
Complementary DNA

Keywords

  • 8-oxo guanine
  • DNA repair
  • MutY
  • Oxidative DNA damage
  • Transversions

ASJC Scopus subject areas

  • Virology

Cite this

Solution structure of a DNA duplex containing 8-hydroxy-2′-deoxyguanosine opposite deoxyguanosine. / Thiviyanathan, Varatharasa; Somasunderam, Anoma; Hazra, Tapas; Mitra, Sankar; Gorenstein, David G.

In: Journal of Molecular Biology, Vol. 325, No. 3, 2003, p. 433-442.

Research output: Contribution to journalArticle

Thiviyanathan, Varatharasa ; Somasunderam, Anoma ; Hazra, Tapas ; Mitra, Sankar ; Gorenstein, David G. / Solution structure of a DNA duplex containing 8-hydroxy-2′-deoxyguanosine opposite deoxyguanosine. In: Journal of Molecular Biology. 2003 ; Vol. 325, No. 3. pp. 433-442.
@article{c9ecfcee9ed844dca0cc594f09231da0,
title = "Solution structure of a DNA duplex containing 8-hydroxy-2′-deoxyguanosine opposite deoxyguanosine",
abstract = "Deoxyguanosine residues are hydroxylated by reactive oxygen species at the C-8 position to form 8-hydroxy-2′-deoxyguanosine (8-OG), one of the most important mutagenic lesions in DNA. Though the spontaneous G:C to C:G transversions are rare events, the pathways leading to this mutation are not established. An 8-OG:G mispair, if not corrected by DNA repair enzymes, could lead to G:C to C:G transversions. NMR spectroscopy and restrained molecular dynamics calculations are used to refine the solution structure of the base mismatch formed by the 8-OG:G pair on a self complementary DNA dodecamer duplex d(CGCGAATT8-O-GGCG)2. The results reveal that the 8-OG base is inserted into the helix) and forms Hoogsteen base-pairing with the G on the opposite strand. The 8-OG:G base-pairs are seen to be stabilized by two hydrogen bonding interactions, one between the H7 of the 8-OG and the O6 of the G, and a three-center hydrogen bonding between the O8 of the 8-OG and the imino and amino protons of the G. The 8-OG:G base-pairs are very well stacked between the Watson-Crick base-paired flanking bases. Both strands of the DNA duplex adopt right-handed conformations. All of the unmodified bases, including the G at the lesion site, adopt anti glycosidic torsion angles and form Watson-Crick base-pairs. At the lesion site, the 8-OG residues adopt syn conformations. The structural studies demonstrate that 8-OG(syn):G(anti) forms a stable pair in the interior of the duplex, providing a basis for the in vivo incorporation of G opposite 8-OG. Calculated helical parameters and backbone torsional angles, and the observed 31P chemical shifts, indicate that the structure of the duplex is perturbed near lesion sites, with the local unwinding of the double helix. The melting temperature of the 8-OG:G containing duplex is only 2.6 deg. C less than the tm of the unmodified duplex.",
keywords = "8-oxo guanine, DNA repair, MutY, Oxidative DNA damage, Transversions",
author = "Varatharasa Thiviyanathan and Anoma Somasunderam and Tapas Hazra and Sankar Mitra and Gorenstein, {David G.}",
year = "2003",
doi = "10.1016/S0022-2836(02)01272-X",
language = "English (US)",
volume = "325",
pages = "433--442",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Solution structure of a DNA duplex containing 8-hydroxy-2′-deoxyguanosine opposite deoxyguanosine

AU - Thiviyanathan, Varatharasa

AU - Somasunderam, Anoma

AU - Hazra, Tapas

AU - Mitra, Sankar

AU - Gorenstein, David G.

PY - 2003

Y1 - 2003

N2 - Deoxyguanosine residues are hydroxylated by reactive oxygen species at the C-8 position to form 8-hydroxy-2′-deoxyguanosine (8-OG), one of the most important mutagenic lesions in DNA. Though the spontaneous G:C to C:G transversions are rare events, the pathways leading to this mutation are not established. An 8-OG:G mispair, if not corrected by DNA repair enzymes, could lead to G:C to C:G transversions. NMR spectroscopy and restrained molecular dynamics calculations are used to refine the solution structure of the base mismatch formed by the 8-OG:G pair on a self complementary DNA dodecamer duplex d(CGCGAATT8-O-GGCG)2. The results reveal that the 8-OG base is inserted into the helix) and forms Hoogsteen base-pairing with the G on the opposite strand. The 8-OG:G base-pairs are seen to be stabilized by two hydrogen bonding interactions, one between the H7 of the 8-OG and the O6 of the G, and a three-center hydrogen bonding between the O8 of the 8-OG and the imino and amino protons of the G. The 8-OG:G base-pairs are very well stacked between the Watson-Crick base-paired flanking bases. Both strands of the DNA duplex adopt right-handed conformations. All of the unmodified bases, including the G at the lesion site, adopt anti glycosidic torsion angles and form Watson-Crick base-pairs. At the lesion site, the 8-OG residues adopt syn conformations. The structural studies demonstrate that 8-OG(syn):G(anti) forms a stable pair in the interior of the duplex, providing a basis for the in vivo incorporation of G opposite 8-OG. Calculated helical parameters and backbone torsional angles, and the observed 31P chemical shifts, indicate that the structure of the duplex is perturbed near lesion sites, with the local unwinding of the double helix. The melting temperature of the 8-OG:G containing duplex is only 2.6 deg. C less than the tm of the unmodified duplex.

AB - Deoxyguanosine residues are hydroxylated by reactive oxygen species at the C-8 position to form 8-hydroxy-2′-deoxyguanosine (8-OG), one of the most important mutagenic lesions in DNA. Though the spontaneous G:C to C:G transversions are rare events, the pathways leading to this mutation are not established. An 8-OG:G mispair, if not corrected by DNA repair enzymes, could lead to G:C to C:G transversions. NMR spectroscopy and restrained molecular dynamics calculations are used to refine the solution structure of the base mismatch formed by the 8-OG:G pair on a self complementary DNA dodecamer duplex d(CGCGAATT8-O-GGCG)2. The results reveal that the 8-OG base is inserted into the helix) and forms Hoogsteen base-pairing with the G on the opposite strand. The 8-OG:G base-pairs are seen to be stabilized by two hydrogen bonding interactions, one between the H7 of the 8-OG and the O6 of the G, and a three-center hydrogen bonding between the O8 of the 8-OG and the imino and amino protons of the G. The 8-OG:G base-pairs are very well stacked between the Watson-Crick base-paired flanking bases. Both strands of the DNA duplex adopt right-handed conformations. All of the unmodified bases, including the G at the lesion site, adopt anti glycosidic torsion angles and form Watson-Crick base-pairs. At the lesion site, the 8-OG residues adopt syn conformations. The structural studies demonstrate that 8-OG(syn):G(anti) forms a stable pair in the interior of the duplex, providing a basis for the in vivo incorporation of G opposite 8-OG. Calculated helical parameters and backbone torsional angles, and the observed 31P chemical shifts, indicate that the structure of the duplex is perturbed near lesion sites, with the local unwinding of the double helix. The melting temperature of the 8-OG:G containing duplex is only 2.6 deg. C less than the tm of the unmodified duplex.

KW - 8-oxo guanine

KW - DNA repair

KW - MutY

KW - Oxidative DNA damage

KW - Transversions

UR - http://www.scopus.com/inward/record.url?scp=0037229050&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037229050&partnerID=8YFLogxK

U2 - 10.1016/S0022-2836(02)01272-X

DO - 10.1016/S0022-2836(02)01272-X

M3 - Article

VL - 325

SP - 433

EP - 442

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 3

ER -