Mechanisms of DNA damage, repair, and mutagenesis.

Our research is based upon the belief that if we understand the mechanisms of cellular processes involved in mutagenesis and carcinogenesis we can design strategies for the prevention or treatment of cancer.

DNA Damage Response

We have examined the mechanism by which DNA adducts formed by tobacco carcinogens produce mutations.  Our approach is three-fold.  First, we synthesize the damaged nucleoside so that we can make oligonucleotides containing the damage.  Second, we study the kinetics with DNA polymerases to understand the relative activities.  Third, we examine the activity and mutagencity in cells.  With this methodology we have shown how O²-POB-dT, a long-lived DNA adduct formed from the tobacco carcinogen NNK, is bypassed by DNA polymerase η.

DNA Polymerase Mechanism

DNA polymerases are remarkable enzymes, catalyzing high fidelity replication on four different substrates despite the fact that the selection criteria is over 10 Å away from the catalytic action.  We have used atomic substitution to probe critical interaction between the polymerase and DNA.