The sacrificial role of easily oxidizable sites in the protection of DNA from damage

It has been suggested that DNA contains sacrificial nucleobase sequences that protect sensitive regions of the genome from oxidative damage. Oxidation of DNA by loss of an electron generates a radical cation that can migrate long distances by hopping. The radical cation can be trapped irreversibly at certain sites (GG steps) by reaction with H2O or O2 leading to the formation of lesions (oxidative damage). A series of DNA oligomers that contain regularly spaced GG steps and an 8-oxo-7,8-dihydroguanine (8-oxoG), which serves as a proxy for possibly sacrificial protective low oxidation potential sites, was prepared and analyzed. We find that in certain special sequences of DNA nucleobases that 8-oxoG protects remote GG steps from oxidative damage but that this is not a general phenomenon extending to normal mixed sequence DNA. This is a consequence of the change in the relative rate of charge hopping compared with trapping of the radical cation. When hopping is relatively slow, 8-oxoG exerts no protective effect. Thus, it seems unlikely that low oxidation potential sequences play a meaningful part in protecting mixed sequence DNA from damage.

[1]  P. Cullis,et al.  Guanine radical cations are precursors of 7,8-dihydro-8-oxo-2'-deoxyguanosine but are not precursors of immediate strand breaks in DNA , 1996 .

[2]  N. Geacintov,et al.  Oxidative DNA Damage Associated with Combination of Guanine and Superoxide Radicals and Repair Mechanisms via Radical Trapping* , 2004, Journal of Biological Chemistry.

[3]  B. Giese.  Long-distance electron transfer through DNA. , 2002, Annual review of biochemistry.

[4]  D. Ly,et al.  Cleavage of DNA by Irradiation of Substituted Anthraquinones: Intercalation Promotes Electron Transfer and Efficient Reaction at GG Steps , 1996 .

[5]  K. A. Friedman,et al.  Guanosine distribution and oxidation resistance in eight eukaryotic genomes. , 2004, Journal of the American Chemical Society.

[6]  Rigoberto Hernandez,et al.  Mechanism for radical cation transport in duplex DNA oligonucleotides. , 2004, Journal of the American Chemical Society.

[7]  A. Heller.  Spiers Memorial Lecture. On the hypothesis of cathodic protection of genes. , 2000, Faraday discussions.

[8]  G. Hampikian,et al.  Long-distance charge transport in duplex DNA: the phonon-assisted polaron-like hopping mechanism. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Adam Heller,et al.  On the non-uniform distribution of guanine in introns of human genes: Possible protection of exons against oxidation by proximal intron poly-G sequences , 2001 .

[10]  D. Beratan,et al.  Long-Range Charge Transfer in DNA II , 2004 .

[11]  P. Henderson,et al.  Bulged Guanine is Uniquely Sensitive to Damage Caused by Visible‐Light Irradiation of Ethidium Bound to DNA: A Possible Role in Mutagenesis , 2002 .

[12]  G. Schuster,et al.  Long-range charge transfer in DNA: transient structural distortions control the distance dependence. , 2000, Accounts of chemical research.

[13]  G. Schuster,et al.  Intramolecular Photoinduced Electron Transfer to Anthraquinones Linked to Duplex DNA: The Effect of Gaps and Traps on Long-Range Radical Cation Migration , 1997 .

[14]  S. Loft,et al.  Role of oxidative DNA damage in cancer initiation and promotion. , 1998, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[15]  S. Boiteux,et al.  Repair of 8-oxoguanine in Saccharomyces cerevisiae: interplay of DNA repair and replication mechanisms. , 2002, Free radical biology & medicine.

[16]  M. Chung,et al.  8‐Oxoguanine induces intramolecular DNA damage but free 8‐oxoguanine protects intermolecular DNA from oxidative stress , 2004, FEBS letters.

[17]  D. Gray,et al.  Absorption and circular dichroism spectroscopy of nucleic acid duplexes and triplexes. , 1995, Methods in enzymology.

[18]  J. Cadet,et al.  Formation of Modified DNA Bases in Cells Exposed either to Gamma Radiation or to High-LET Particles1 , 2002, Radiation research.

[19]  Jacqueline K Barton,et al.  DNA charge transport: conformationally gated hopping through stacked domains. , 2004, Journal of the American Chemical Society.

[20]  Paul M Johnson,et al.  Antioxidant-induced changes in oxidized DNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Adhikary,et al.  Formation of 8-oxo-7,8-dihydroguanine-radicals in γ-irradiated DNA by multiple one-electron oxidations , 2007, Nucleic acids research.

[22]  J. Cadet,et al.  One-electron oxidation of the guanine moiety of 2'-deoxyguanosine: influence of 8-oxo-7,8-dihydro-2'-deoxyguanosine. , 2003, Journal of the American Chemical Society.

[23]  C. Foote,et al.  SOLVENT AND ELECTRONIC EFFECTS ON THE REACTION OF GUANOSINE DERIVATIVES WITH SINGLET OXYGEN , 1995 .

[24]  Mark A. Ratner,et al.  On the Long-Range Charge Transfer in DNA , 2000 .

[25]  M. Wasielewski,et al.  Dynamics and Equilibria for Oxidation of G, GG, and GGG Sequences in DNA Hairpins , 2000 .

[26]  L. A. Lipscomb,et al.  X-ray structure of a DNA decamer containing 7,8-dihydro-8-oxoguanine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.