Bypass of dG-AAF by human polymerase ι : Molecular dynamics studies

TOXI 52

Kerry P. Donny-Clark, kpd200@nyu.edu1, Lihua Wang1, Robert Shapiro, rs2@nyu.edu2, and Suse Broyde, broyde@nyu.edu1. (1) Department of Biology, New York University, 100 Washington Sqare East, 1009 Silver Center, New York, NY 10003, (2) Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003
Crystal structures of human DNA polymerase ι (pol ι), a Y-family bypass polymerase, show a ternary complex with a syn templating base forming Hoogsteen hydrogen bonds with the incoming nucleotide triphosphate (Nair et al. 2004, 2005, 2006). Primer extension studies reveal that pol ι predominantly inserts the correct partner opposite dG with a C8-linked N-2-acetylaminofluorene(dG-AAF) adduct. We have performed molecular dynamics studies of dG-AAF in pol ι to evaluate possible favored locations of the adduct in the enzyme. Our simulations suggest that the damaged dG can avoid disrupting the active site by assuming an anti conformation, forming three Watson-Crick hydrogen bonds with the incomer. Models with the templating dG syn, as is necessary for Hoogsteen bonding, cause severe distortion of the active site. Our findings suggest that pol ι can use Watson-Crick bonding to insert the dCTP opposite dG-AAF. This work supported by NIH CA75449.

 

Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster

Division of Chemical Toxicology

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