Structure-function relationships in the recognition and DNA repair of bulky lesions by the human nucleotide excision repair apparatus

TOXI 131

N. E. Geacintov, ng1@nyu.edu1, Konstantin Kropachev, kk58@nyu.edu2, Marina Kolbanovskiy2, Fabian A. Rodriguez, far217@nyu.edu1, Yuqin Cai, yc385@nyu.edu1, Lu Zhang, lz365@nyu.edu2, Yijin Tang, yt316@nyu.edu1, Alexander Kolbanovskiy, ak19@nyu.edu1, Dinshaw J Patel, pateld@mskcc.org3, and Suse Broyde, broyde@nyu.edu4. (1) Department of Chemistry, New York University, 31 Washington Pl, New York, NY 10003-5180, (2) Chemistry Department, New York University, New York, NY 10003-5180, (3) Cellular Biochemistry & Biophysics Program, Memorial Sloan-Kattering Cancer Center, 1275 York Avenue, New York, NY 10021, (4) Department of Biology, New York University, 100 Washington Square East, New York, NY 10003
The removal of bulky DNA lesions by nucleotide excision repair (NER) mechanisms is an important line of defense against the genotoxic effects of a variety of chemicals. The diol epoxide anti-B[a]PDE derived from benzo[a]pyrene is highly mutagenic. Mutation hotspots associated with the formation of (+)-trans-B[a]P-N2-dG (G*) adducts in DNA are frequently found in runs of guanines (GG). DNA repair of these bulky lesions depends on base sequence context and may contribute to the mutation hotspot phenomena by efficiently excising lesions in some sequence contexts but not in others. Here, we have compared the nucleotide excision repair in human HeLa cell-free extracts of the identical adducts G* embedded in CG*GC, CGG*C, and CG*C sequence contexts in 135-mer duplexes. Although NMR methods reveal that the B[a]P aromatic ring system is positioned in the minor groove (5'-directed relative to G*) in all three cases, the susceptibilities of these lesions to NER decrease in the order CG*GC > CGG*C > CG*C. These NER efficiencies are correlated with the structural characteristics of the lesions and the base sequence-dependent DNA structural perturbations they cause. Supported by NIH CA 099194 and CA 28038.
 

General Papers
1:00 PM-4:45 PM, Wednesday, August 22, 2007 BCEC -- 258C, Oral

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007