Effects of benzo[a]pyrene adduct stereochemistry on downstream DNA replication in vitro: evidence for different adduct conformations within the active site of DNA polymerase I (Klenow fragment)

Biochemistry
Y O Alekseyev, Louis J Romano

Abstract

The presence of bulky adducts in DNA is known to interfere with DNA replication not only at the site of the lesion but also at positions up to 5 nucleotides past the adduct location. Kinetic studies of primer extension by exonuclease-deficient E. coli DNA polymerase I (Klenow fragment) (KF) when (+)-trans- or (+)-cis-B[a]P-N(2)-dG adducts were positioned in the double-stranded region of the primer-templates showed that both stereoisomers significantly block downstream replication. However the (+)-cis adduct, which causes a stronger inhibition of the nucleotides insertion across from and immediately past the lesion, affected the downstream replication to a much smaller extent than did the (+)-trans adduct, especially when the B[a]P-modified dG was properly paired with a dC. The effects of mismatches across from the adduct and the sequence context surrounding the adduct were also dependent on the stereochemistry of the B[a]P adduct. Thus, the identity of the nucleotide across from the adduct that provided the best downstream replication was different for the (+)-cis and (+)-trans adducts, a factor that might differentially contribute to the mutagenic bypass of these lesions. These findings provide strong direct evidence that the ...Continue Reading

Citations

Nov 18, 2005·Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews·Bongsup P Cho
Jan 13, 2015·The Journal of Organic Chemistry·Pratibha P GhodkeP I Pradeepkumar
Nov 19, 2004·The Journal of Biological Chemistry·Gerald W HsuLorena S Beese
Apr 10, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Zhixiang WuJianping Hu

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