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Trapping of DNA Nucleotide Excision Repair Factors by Nonrepairable Carcinogen Adducts¹

Institute of Pharmacology and Toxicology, University of Zürich-Tierspital, CH-8008 Zürich, Switzerland [T. B., M. T. H., D. G., H. N.]; Chemistry Department, New York University, New York, New York 10003 [N. E. G.]; and Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, 2333 AL Leiden, the Netherlands [L. H. M.]

Nucleotide excision repair is part of a cellular defense system that protects genome integrity.Here, this versatile repair system was challenged with mixtures of DNA adducts that were generated to mimic the wide spectrum of bulky lesions produced by complex genotoxic insults. Probing human excision activity with substrate combinations instead of single lesions resulted in a strong bias for particular base adducts, such that the repair factors were immobilized on a small fraction of damaged DNA, whereas the simultaneous excision of other sites was suppressed. Immobilization of excision factors was also induced by nonrepairable decoy adducts, thereby revealing a mechanism of repair inhibition because of hijacking of critical subunits. Thus, the efficiency of excision repair in response to bulky carcinogen-DNA damage is dependent on an antagonistic interaction with both substrate and decoy adducts.

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