| WELCOME!
The unifying goal of this Program Project is to understand mechanisms by which exposures to environmentally- and endogenously-produced bis-electrophiles, such as vinyl chloride, acrolein, crotonaldehyde, and 4-hydroxynonenal (4-HNE), induce genotoxic response, ultimately impacting human health. Our work has demonstrated that adduction of DNA by aldehydic bis-electrophiles yields interstrand crosslinks, intrastrand crosslinks, DNA-protein conjugates, and various regioisomeric mono-adducts. These interfere with DNA processing, leading to mutagenesis and cytotoxicity. The abilities of environmentally and endogenously generated bis-electrophiles to form DNA-DNA and DNA-protein crosslinks are anticipated to be of particular significance with regard to human health. These compounds likely contribute to background levels of inter- and intrastrand crosslinks and DNA-protein crosslinks formed in human cells.
This Program Project is funded by the National Institute of Environmental Health Sciences (NIEHS) and consists of three sub-projects. Project 1, led by Professor Carmelo Rizzo at Vanderbilt University, develops synthetic routes to construct oligodeoxynucleotides containing site- and stereospecific adducts, investigates the in vitro replication bypass and secondary chemical reactivity of these adducts, and works to identify these adducts in cellular DNA. Project 2, led by Professor R. Stephen Lloyd at the Oregon Health and Science University, generates biological endpoints with respect to replication, repair, and mutagenesis in response to the introduction into cells of site-specific lesions. Project 3, led by Professor Michael Stone at Vanderbilt University, provides structural information for these adducted oligodeoxynucleotides using combined of NMR and X-ray crystallographic approaches, delineating solution dynamics and equilibria and interactions of modified DNA templates with bypass polymerases. The DNA Synthesis Core, located at Vanderbilt University and under the direction of Professor Ivan Kozekov, provides service of outstanding value to all projects. In addition, the Core has provided unique samples to other investigators as a professional courtesy or formal collaboration with this program project.
|
|
