MECHANISMS OF MUTAGENESIS BY CYCLIC DNA ADDUCTS

Project Details

Description

The major aim of this proposal is to investigate the mechanisms
of mutagenesis by cyclic DNA adducts induced by metabolites of
the carcinogen vinyl chloride. Our preliminary data imply that
etheno-cytosine (sigma C) preferentially incorporates A residues
in vivo leading to C-to-T transitions. Hydrated lesions are less
mutagenic, but appear to have the same specificity. Our results
point to two major categories of mechanisms for etheno adduct
mutagenesis: a) Etheno lesions are essentially non-instructional in
vivo. Mutagenesis opposite these lesions arises due to 'non-
specific' insertion by polymerase, possibly aided by stacking
interactions expected of these planar lesions. Included in this
category of mechanisms is the possibility that etheno derivatives
are converted to abasic sites in vivo. b) Etheno derivatives have
in vivo miscoding properties which are distinct from miscoding
properties observed by others in vitro. In order to test the above
and other mechanisms, we propose the following experiments.
1. The effect of genetic parameters on repair and mutagenesis:
specifically, the effects of RecA, SOS and excision repair. This
information is essential for a more complete interpretation of our
present data.
2. Response of the above genetic parameters to hydrated etheno
lesions.
3. Site-specific in vivo and in vitro experiments. The in vivo
experiments will confirm present sigma C data by more exacting
approaches, specifically test the mutagenicity of sigma A and will
test a prediction in the literature that sigma A may cause 1 bp
deletions. The in vitro site-specific experiments are aimed at a
more detailed understanding of events associated with bypass of
sigma C and Sigma A.
In addition to the above experiments, a search for E. coli N-
glycosylases capable of acting on etheno lesions will be mounted
in later stages. We propose to develop and use sensitive
immunoassays during the course of the above studies.
StatusFinished
Effective start/end date5/1/884/30/93

Funding

  • National Institutes of Health
  • National Institutes of Health: $122,740.00
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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