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Nucleic Acids Research Advance Access published online on October 17, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn719
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

The N-clasp of human DNA polymerase {kappa} promotes blockage or error-free bypass of adenine- or guanine-benzo[a]pyrenyl lesions

Lei Jia1, Nicholas E. Geacintov2 and Suse Broyde1,2,*

1Department of Biology and 2Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003, USA

*To whom correspondence should be addressed: Tel: +1 212 998 8231; Fax: +1 212 995 4015; Email: broyde{at}nyu.edu

Received August 22, 2008. Revised September 29, 2008. Accepted September 30, 2008.

DNA bypass polymerases are utilized to transit bulky DNA lesions during replication, but the process frequently causes mutations. The structural origins of mutagenic versus high fidelity replication in lesion bypass is therefore of fundamental interest. As model systems, we investigated the molecular basis of the experimentally observed essentially faithful bypass of the guanine 10S-(+)-trans-anti-benzo[a]pyrene-N2-dG adduct by the Y-family human DNA polymerase {kappa}, and the observed blockage of pol {kappa} produced by the adenine 10S-(+)-trans-anti-benzo[a]pyrene-N2-dA adduct. These lesions are derived from the most tumorigenic metabolite of the ubiquitous cancer-causing pollutant, benzo[a]pyrene. We compare our results for the dG adduct with our earlier studies for the pol {kappa} archaeal homolog Dpo4, which processes the same lesion in an error-prone manner. Molecular modeling, molecular mechanics calculations and molecular dynamics simulations were utilized. Our results show that the pol {kappa} N-clasp is a key structural feature that accounts for the dA adduct blockage and the near-error-free bypass of the dG lesion. Absence of the N-clasp in Dpo4 explains the error-prone processing of the same lesion by this enzyme. Thus, our studies elucidate structure-function relationships in the fidelity of lesion bypass.


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