Molecular Carcinogenesis: Mechanisms of DNA Repair and Mutagenesis in Mammalian Cells

Arthur P. Grollman, M.D.
Professor, Pharmacological Sciences
Distinguished Professor
Evelyn G. Glick Professor of Experimental Medicine
Director:  Laboratory for Chemical Biology
M.D., Johns Hopkins University School of Medicine

Recent studies in this laboratory established the miscoding effects of oxidative DNA damage and defined an important error-avoidance pathway that protects cells against mutations produced by 8-oxoguanine. We continue to focus on the biological consequences of DNA damage, with particular reference to molecular mechanisms of DNA replication, mutagenesis, and repair. Using site-specific methods, we are exploring the mutagenic potential of defined DNA lesions in mammalian cells. Shuttle plasmid vectors are used to establish the efficiency and fidelity of translesional synthesis and mechanisms of recombinational repair. Mutational events also are studied in vitro with primer-extension reactions catalyzed by DNA polymerases. The three-dimensional structure of DNA glycosylases bound to their cognate DNA substrates, as established by x-ray crystallographic techniques, are being used to correlate molecular structure with enzymatic function.

Selected Papers

Rosenquist, T., Zharkov, D.O., and Grollman, A.P.  Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase.  Proc. Natl. Acad. Sci. USA 94, 7429-7434 (1997).

Zharkov, D.O. and Grollman, A.P.  MutY DNA glycosylase:  base release and intermediate complex formation. Biochemistry 37, 12384-12394 (1998).

Shibutani, S., Fernandes, A., Suzuki, N., Zhou, L., Johnson, F., and Grollman, A.P. Mutagenesis of the N-(deoxyguanosin-8-yl-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine DNA adduct in mammalian cells. J. Biol. Chem. 274, 27433-27438 (1999).

Shibutani, S., Ravindernath, A., Suzuki, N., Terashima, I., Sugarman, S.M., Grollman, A.P., and Pearl, M.L. Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen. Carcinogenesis 21, 1461-1467 (2000).

Miller, H., Prasad, R., Wilson, S.H., Johnson, F., and Grollman, A.P.  8-OxoGTP incorporation by DNA polymerase b is modified by active-site residue ASN279.  Biochemistry 39, 1029-1033 (2000).

Zharkov, D.O., Rosenquist, T.A., Gerchman, S.E., and Grollman, A.P. Substrate specificity and reaction mechanism of murine 8-oxoguanine-DNA glycosylase. J. Biol. Chem. 275, 28607-28617 (2000).

Complete List of Publications