Arylhydrazine carcinogenesis and the synthesis of C8-arylpurine oligonucleotides [electronic resource] : a study of DNA adduct affects on DNA conformation and stability /
Arylhydrazine Carcinogenesis and the Synthesis of C8-Arylpurine Oligonucleotides:
A Study of DNA Adduct Effects on DNA Conformation and Stability
Jonathan R. Daft
Agaricus bisporus mushrooms have been shown to be carcinogenic due to their
arylhydrazine content, but the mechanism of the carcinogenesis has not been elucidated. Clues
into the mechanism have been discovered in the metabolism of the arylhydrazines to
arenediazonium ions and aryl radicals. Both of these compounds form DNA adducts, which may
be relevant to carcinogenesis.
Arenediazonium ions have been shown to activate signal transduction proteins associated
with DNA damage and apoptosis. Previously, our group had shown that arenediazonium ions
activate the apoptotic protein AP1. The activation of AP1 has been correlated to aryl radial
generation, since the AP1 activation can be rescued with carbon radical scavengers but not
oxygen radical scavengers.
The studies reported herein takes the signal transduction pathways a step further and
shows that arenediazonium ions activate the DNA damage signaling protein p53. This would
imply that the aryl radicals are causing a significant amount of DNA damage, which cells
attempt to repair. Since the aryl radicals are known to form C8-arylpurine DNA adducts, it will
be important to study the affects of those DNA adducts specifically.
The role of C8-arylpurine DNA adducts in the mechanism of arylhydrazine
carcinogenesis has also been addressed in relation to DNA conformation and stability. Thermal
denaturation, circular dichroism, and nuclear magnetic resonance were used to study modified
oligonucleotides. The C8-arylpurine modified oligonucleotides exhibited distinct changes in
conformation and duplex stability.
The results from the study of DNA damage and C8-arylpurine DNA adduct affects
indicate that C8-arylpurines are a major contributor in arylhydrazine carcinogenesis. Since aryl
radials appear to cause the apoptotic and DNA damage responses, C8-arylpurines are implicated
into the mechanism of carcinogenesis. Data showing that C8-arylpurines alter DNA
conformation and duplex stability identifies that these DNA adducts will affect DNA-protein
binding and DNA decomposition. Both effects could lead to an increase in DNA mutations,
which may be the mechanism behind arylhydrazine carcinogenesis.
School:West Virginia University
School Location:USA - West Virginia
Source Type:Master's Thesis
Keywords:carcinogenesis dna adducts oligonucleotides cultivated mushroom carcinogens agaricus
Date of Publication: