This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buterin, T. Articles by Naegeli, H. Search for Related Content PubMed PubMed Citation Articles by Buterin, T. Articles by Naegeli, H.

Unrepaired Fjord Region Polycyclic Aromatic Hydrocarbon-DNA Adducts in ras Codon 61 Mutational Hot Spots¹

Institute of Pharmacology and Toxicology, University of Zürich-Tierspital, CH-8008 Zürich, Switzerland [T. B., M. T. H., H. N.]; Chemistry Department, New York University, New York, New York 10003 [N. L., N. E. G.]; American Health Foundation, Valhalla, New York 10595 [S. A.]; and Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany [H. K., A. S.]

The fjord region diol-epoxide metabolites of polycyclic aromatic hydrocarbons display stronger tumorigenic activities in rodent studies than comparable bay region diol-epoxides, but the molecular basis for this difference between fjord and bay region derivatives is not understood. Here we tested whether the variable effects of these genotoxic metabolites of polycyclic aromatic hydrocarbons may result from different DNA repair reactions. In particular, we compared the repairability of DNA adducts formed by bay region benzo[a]pyrene (B[a]P) diol-epoxides and the structurally similar but significantly more tumorigenic fjord region diol-epoxide metabolites of benzo[c]phenanthrene (B[c]Ph). For that purpose, we incorporated both types of polycyclic aromatic hydrocarbon adducts into known hot spot sites for carcinogen-induced proto-oncogene activation. Synthetic DNA substrates were assembled using a portion of human N-ras or H-ras that includes codon 61, and stereospecific B[a]P or B[c]Ph adducts were synthesized on adenine N⁶ at the second position of these two ras codon 61 sequences. DNA repair was determined by incubating the site-directed substrates in human cell extracts, followed by electrophoretic visualization of radiolabeled oligonucleotide excision products. These cell-free assays showed that all tested bay region B[a]P-N⁶-dA adducts are removed by the human nucleotide excision repair system, although excision efficiency varied with the particular stereochemical configuration of each B[a]P residue. In contrast, all fjord region B[c]Ph-N⁶-dA adducts located in the identical sequence context and with exactly the same stereochemical properties as the corresponding B[a]P lesions were refractory to the nucleotide excision repair process. These findings indicate that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol-epoxides may be attributed, at least in part, to slow repair of the stable base adducts deriving from the reaction of these compounds with DNA.

This article has been cited by other articles:

				M. C. Caino, J. L. Oliva, H. Jiang, T. M. Penning, and M. G. Kazanietz Benzo[a]pyrene-7,8-dihydrodiol Promotes Checkpoint Activation and G2/M Arrest in Human Bronchoalveolar Carcinoma H358 Cells Mol. Pharmacol., March 1, 2007; 71(3): 744 - 750. [Abstract] [Full Text] [PDF]

				V. K. Batra, D. D. Shock, R. Prasad, W. A. Beard, E. W. Hou, L. C. Pedersen, J. M. Sayer, H. Yagi, S. Kumar, D. M. Jerina, et al. Structure of DNA polymerase beta with a benzo[c]phenanthrene diol epoxide-adducted template exhibits mutagenic features PNAS, November 14, 2006; 103(46): 17231 - 17236. [Abstract] [Full Text] [PDF]

				S. Choudhary, K. M. Doherty, C. J. Handy, J. M. Sayer, H. Yagi, D. M. Jerina, and R. M. Brosh Jr. Inhibition of Werner Syndrome Helicase Activity by Benzo[a]pyrene Diol Epoxide Adducts Can Be Overcome by Replication Protein A J. Biol. Chem., March 3, 2006; 281(9): 6000 - 6009. [Abstract] [Full Text] [PDF]

				J.-H. Yoon, A. Besaratinia, Z. Feng, M.-s. Tang, S. Amin, A. Luch, and G. P. Pfeifer DNA Damage, Repair, and Mutation Induction by (+)-Syn and (-)-Anti-Dibenzo[a,l]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells Cancer Res., October 15, 2004; 64(20): 7321 - 7328. [Abstract] [Full Text] [PDF]

				I. Gomez-Pinto, E. Cubero, S. G. Kalko, V. Monaco, G. van der Marel, J. H. van Boom, M. Orozco, and C. Gonzalez Effect of Bulky Lesions on DNA: SOLUTION STRUCTURE OF A DNA DUPLEX CONTAINING A CHOLESTEROL ADDUCT J. Biol. Chem., June 4, 2004; 279(23): 24552 - 24560. [Abstract] [Full Text] [PDF]

				H. C. Driscoll, S. W. Matson, J. M. Sayer, H. Kroth, D. M. Jerina, and R. M. Brosh Jr. Inhibition of Werner Syndrome Helicase Activity by Benzo[c]phenanthrene Diol Epoxide dA Adducts in DNA Is Both Strand-and Stereoisomer-dependent J. Biol. Chem., October 17, 2003; 278(42): 41126 - 41135. [Abstract] [Full Text] [PDF]

				T. M. Schinecker, R. A. Perlow, S. Broyde, N. E. Geacintov, and D. A. Scicchitano Human RNA polymerase II is partially blocked by DNA adducts derived from tumorigenic benzo[c]phenanthrene diol epoxides: relating biological consequences to conformational preferences Nucleic Acids Res., October 15, 2003; 31(20): 6004 - 6015. [Abstract] [Full Text] [PDF]

				D. R. Lloyd and P. C. Hanawalt p53 Controls Global Nucleotide Excision Repair of Low Levels of Structurally Diverse Benzo(g)chrysene-DNA Adducts in Human Fibroblasts Cancer Res., September 15, 2002; 62(18): 5288 - 5294. [Abstract] [Full Text] [PDF]

				M. Wu, S. Yan, D. J. Patel, N. E. Geacintov, and S. Broyde Relating repair susceptibility of carcinogen-damaged DNA with structural distortion and thermodynamic stability Nucleic Acids Res., August 1, 2002; 30(15): 3422 - 3432. [Abstract] [Full Text] [PDF]

				Y. Pommier, G. Kohlhagen, G. S. Laco, H. Kroth, J. M. Sayer, and D. M. Jerina Different Effects on Human Topoisomerase I by Minor Groove and Intercalated Deoxyguanosine Adducts Derived from Two Polycyclic Aromatic Hydrocarbon Diol Epoxides at or Near a Normal Cleavage Site J. Biol. Chem., April 12, 2002; 277(16): 13666 - 13672. [Abstract] [Full Text] [PDF]

				B. Mahadevan, A. Luch, A. Seidel, J. C. Pelling, and W. M. Baird Effects of the (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of dibenzo[a,l]pyrene on DNA adduct formation and cell cycle arrest in human diploid fibroblasts Carcinogenesis, January 1, 2001; 22(1): 161 - 169. [Abstract] [Full Text] [PDF]