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Replication past a trans-4-Hydroxynonenal Minor-Groove Adduct by the Sequential Action of Human DNA Polymerases and

Sealy Center for Molecular Science, University of Texas Medical Branch at Galveston, 6.104 Blocker Medical Research Building, 11th and Mechanic Streets, Galveston, Texas 77555-1061,¹ Center for Research in Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97239²

Received 8 September 2005/ Returned for modification 7 October 2005/ Accepted 13 October 2005

The X-ray crystal structure of human DNA polymerase (Pol) has shown that it differs from all known Pols in its dependence upon Hoogsteen base pairing for synthesizing DNA. Hoogsteen base pairing provides an elegant mechanism for synthesizing DNA opposite minor-groove adducts that present a severe block to synthesis by replicative DNA polymerases. Germane to this problem, a variety of DNA adducts form at the N² minor-groove position of guanine. Previously, we have shown that proficient and error-free replication through the -HOPdG (-hydroxy-1,N²-propano-2'-deoxyguanosine) adduct, which is formed from the reaction of acrolein with the N² of guanine, is mediated by the sequential action of human Pol and Pol, in which Pol incorporates the nucleotide opposite the lesion site and Pol carries out the subsequent extension reaction. To test the general applicability of these observations to other adducts formed at the N² position of guanine, here we examine the proficiency of human Pol and Pol to synthesize past stereoisomers of trans-4-hydroxy-2-nonenal-deoxyguanosine (HNE-dG). Even though HNE- and acrolein-modified dGs share common structural features, due to their increased size and other structural differences, HNE adducts are potentially more blocking for replication than -HOPdG. We show here that the sequential action of Pol and Pol promotes efficient and error-free synthesis through the HNE-dG adducts, in which Pol incorporates the nucleotide opposite the lesion site and Pol performs the extension reaction.

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