Guanine and 7,8-dihydro-8-oxo-guanine-specific oxidation in DNA by chromium(V).
The hexavalent oxidation state of chromium [Cr(VI)] is a well-established human carcinogen, although the mechanism of cancer induction is currently unknown. Intracellular reduction of Cr(VI) forms Cr(V), which is thought to play a fundamental role in the mechanism of DNA damage by this carcinogen. Two separate pathways of DNA damage, an oxidative pathway and a metal-binding pathway, have been proposed to account for the lesions observed in cell systems. We have used a model Cr(V) complex, N,N-ethylenebis(salicylidene-animato)oxochromium(V) [Cr(V)-Salen], to investigate the oxidative pathway of DNA damage and to elucidate the lesions generated from this oxidation process. Reaction of Cr(V)-Salen with synthetic oligonucleotides produced guanine-specific lesions that were not 8-oxo-2'-deoxyguanosine, based on the inability of iridium(IV) to further oxidize these sites. Oxidation products were identified using a 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-G) containing oligonucleotide to increase the yields of product for identification by electrospray ionization mass spectrometry. The guanine-based lesions observed by mass spectrometry corresponded to the lesions guanidinohydantoin and spiroiminodihydantoin. The effects of these Cr(V)-Salen-induced lesions on DNA replication fidelity was assayed using a polymerase-based misincorporation assay. These lesions produced G --> T transversion mutations and polymerase stops at levels greater than those observed for 8-oxo-G. These data suggest a model by which chromate can cause DNA damage leading to mutations and cancer.
Sugden
Kent D
KD
Department of Chemistry, The University of Montana, 32 Campus Drive, Missoula, MT 59812, USA. sugden@selway.umt.edu
Martin
Brooke D
BD
D002274:Carcinogens, Environmental / Q000009:adverse effects* / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D002857:Chromium / Q000009:adverse effects* / Q000737:chemistry; D004249:DNA Damage; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase / Q000494:pharmacology; D005029:Ethylenediamines / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D009841:Oligonucleotides; D010084:Oxidation-Reduction
C453560:7,8-dihydro-8-oxoguanine; D002274:Carcinogens, Environmental; D002614:Chelating Agents; D017931:DNA Primers; D005029:Ethylenediamines; D009841:Oligonucleotides; D002857:Chromium; C074702:chromium hexavalent ion; D006147:Guanine; C011452:disalicylaldehyde ethylenediamine; D004259:DNA-Directed DNA Polymerase