Structure of a high fidelity DNA polymerase bound to a benzo[a]pyrene adduct that blocks replication.
Journal Article
Of the carcinogens to which humans are most frequently exposed, the polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) is one of the most ubiquitous. BP is a byproduct of grilled foods and tobacco and fuel combustion and has long been linked to various human cancers, particularly lung and skin. BP is metabolized to diol epoxides that covalently modify DNA bases to form bulky adducts that block DNA synthesis by replicative or high fidelity DNA polymerases. Here we present the structure of a high fidelity polymerase from a thermostable strain of Bacillus stearothermophilus (Bacillus fragment) bound to the most common BP-derived N2-guanine adduct base-paired with cytosine. The BP adduct adopts a conformation that places the polycyclic BP moiety in the nascent DNA minor groove and is the first structure of a minor groove adduct bound to a polymerase. Orientation of the BP moiety into the nascent DNA minor groove results in extensive disruption to the interactions between the adducted DNA duplex and the polymerase. The disruptions revealed by the structure of Bacillus fragment bound to a BP adduct provide a molecular basis for rationalizing the potent blocking effect on replication exerted by BP adducts.
Full Text
Duke Authors
Cited Authors
- Hsu, GW; Huang, X; Luneva, NP; Geacintov, NE; Beese, LS
Published Date
- February 4, 2005
Published In
Volume / Issue
- 280 / 5
Start / End Page
- 3764 - 3770
PubMed ID
- 15548515
Pubmed Central ID
- 15548515
International Standard Serial Number (ISSN)
- 0021-9258
Digital Object Identifier (DOI)
- 10.1074/jbc.M411276200
Language
- eng
Conference Location
- United States