CHEMISTRY AND BIOLOGY OF EXOCYCLIC DNA ADDUCTS

  • Breslauer, Kenneth (PI)
  • Breslauer, Kenneth (PI)
  • Eisenberg, Moises (PI)
  • De Los Santos, Carlos Raul (PI)
  • Johnson, Francis (PI)
  • Iden, Charles (PI)
  • Kisker, Caroline (PI)
  • Grollman, Arthur (PI)
  • De Los Santos, Carlos Raul (PI)
  • Iden, Charles (PI)

Project Details

Description

The research projects comprising this Program are designed to provide
insights into the biological role of exocyclic nucleic acid derivatives in
carcinogenesis. The central theme of this multidisciplinary program
focuses on the relationship of molecular structure to biological function.
By applying experimental systems which reflect mutagenic spectra of a
single species of DNA adduct and by using modern chemical techniques to
establish primary and three-dimensional structures of DNA adducts, we hope
to define fundamental structure-activity relationships that will assist in
elucidating mechanisms of chemical mutagenesis. The specific objectives of this Program research include development of
sensitive and specific methods for detection and quantitation of exocyclic
DNA adducts and determination of the chemical structures of such adducts.
In several studies, we will use synthetic duplex oligodeoxynucleotides as
sequence-defined models for DNA. We also propose to extend the general usefulness of solid-phase DNA
synthesis by developing new nucleoside protecting groups which will permit
site-specific incorporation of alkali-sensitive adducts into oligodeoxynuc-
leotides. Synthetic routes will be designed by which desired exocyclic
adducts and DNA crosslinks can conveniently be prepared. Exocyclic adducts
will be incorporated site-specifically into shuttle vectors and other
genomes and their mutational spectra will be determined in mammalian cells
and bacteria. We will attempt to relate biological properties of exocyclic adducts to
their three-dimensional structure, as determined by two-dimensional NMR and
computer-assisted molecular modelling techniques. Recent developments in
these areas of research make it possible to assign the structure and
conformation, in solution, of duplex DNA containing up to 20 base pairs.
Refinement of certain parameters is required for molecular modelling
studies; we will concentrate our efforts on the general equations governing
solvent terms which will be applied to energy minimization programs used to
model the tertiary structure of DNA.
StatusFinished
Effective start/end date4/1/907/31/10

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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