This is a competitive continuation of a R29 grant which was awarded in 1988. The focus of the work is the study of mutagenesis by a combination of organic chemistry, NMR, and in vitro polymerase methods.
The specific aims are to: 1) study the equilibrium between H-bonding patterns for 5-Br-dU and 2-amino-dpurine at a replication fork model, employing NMR methods. 2) use NMR to study the pseudorotational state of bases at the 3' terminus of a primer strand, at an in vitro model of a replication fork. 3) use NMR to study the equilibrium between syn and anti forms of exocyclic alkyl groups on dG (O6-methyl dG) and dA (N6- methyl dA), again with the replication fork model. 4) use NMR, optical methods and in vitro replication methods to study the mechanism of the high mutational efficiency of 5-OHdC. The modified base will be positioned internal to a blunt ended duplex, rather than in the replication fork model. 5) to use NMR to study the structure of N3- hydroxyalkyl derivatives of dU. The modified base will be positioned internal to a blunt ended duplex, rather than in the replication fork model.
|McLean, Lancelot S; Watkins, Cheri N; Campbell, Petreena et al. (2015) Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells. Chem Res Toxicol 28:855-71|
|Kim, Cherine H; Darwanto, Agus; Theruvathu, Jacob A et al. (2010) Polymerase incorporation and miscoding properties of 5-chlorouracil. Chem Res Toxicol 23:740-8|
|Williams, Adides A; Darwanto, Agus; Theruvathu, Jacob A et al. (2009) Impact of sugar pucker on base pair and mispair stability. Biochemistry 48:11994-2004|
|Theruvathu, Jacob A; Kim, Cherine H; Darwanto, Agus et al. (2009) pH-Dependent configurations of a 5-chlorouracil-guanine base pair. Biochemistry 48:11312-8|
|McLean, Lancelot; Soto, Ubaldo; Agama, Keli et al. (2008) Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. Int J Cancer 122:1665-74|