A number of industrially important metals and carcinogens. Nickel and chromium stand out because they are human and animal carcinogens and also positive in short-term toxicity tests. Beryllium, an animal carcinogen and mutagen, is also positive in short-term tests. The molecular mechanisms by which these three metals act are not known. These metal-DNA interactions will be examined in a series of in vitro and in vivo experiments designed to measure the mechanisms and importance of metals in mutagenesis, DNA damage, polymerase function, and DNA-protein crosslinking. Metal mutagenesis, will be assayed in vitro with the M13mp2 forward-mutation assay using eukaryotic DNA polymerase-alpha. Mutations produced in vitro by the interactions of Be, Ni, or Cr will be quantitated, sequenced, and compared. The metal-induced mutations will be compared with the types of metal-induced DNA damage; base- and/or sequence-specifically will be assessed. Metal-induced nonspecific DNA damage also will be identified as DNA polymerase pause sites. Because DNA polymerase require divalent metal cations for activity and can be adversely affected by the wrong cations, the kinetics of DNA polymerase activity will be determined in the presence of the metal ions using kinetic primer-extension techniques. Since both Ni and Cr produce DNA- protein crosslinking in vitro, the effects of crosslinking on polymerase activity and mutagenesis will be studied using nonsequence-specific DNA binding proteins. Each metal's mutation spectrum will also be analyzed in vivo using an integrated shuttle-vector. Comparison of metal mutagenesis in vivo with the damage and mutation spectrum in vitro will provide evidence of whether the mechanisms are the same or not.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA045664-01
Application #
3458488
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1987-07-06
Project End
1992-05-31
Budget Start
1987-07-06
Budget End
1988-05-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Snow, E T; Xu, L S; Kinney, P L (1993) Effects of nickel ions on polymerase activity and fidelity during DNA replication in vitro. Chem Biol Interact 88:155-73
Snow, E T (1992) Metal carcinogenesis: mechanistic implications. Pharmacol Ther 53:31-65
Snow, E T; Xu, L S (1991) Chromium(III) bound to DNA templates promotes increased polymerase processivity and decreased fidelity during replication in vitro. Biochemistry 30:11238-45
Snow, E T (1991) A possible role for chromium(III) in genotoxicity. Environ Health Perspect 92:75-81
Snow, E T; Xu, L S (1989) Effects of chromium(III) on DNA replication in vitro. Biol Trace Elem Res 21:61-71
Snow, E T; Mitra, S (1988) Role of carcinogen-modified deoxynucleotide precursors in mutagenesis. Mutat Res 200:157-64