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J. Biol. Chem., Vol. 280, Issue 48, 39684-39692, December 2, 2005

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Error-prone Translesion Synthesis by Human DNA Polymerase on DNA-containing Deoxyadenosine Adducts of 7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene^*

Dominic Chiapperino, Mangmang Cai, Jane M. Sayer, Haruhiko Yagi, Heiko Kroth, Chikahide Masutani, Fumio Hanaoka¶, Donald M. Jerina, and Albert M. Cheh||1

From the Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892, ^||Department of Chemistry, American University, Washington, D. C. 20016, ^¶RIKEN and Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Wako, Saitama 351-0198, Japan, and the Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

When human DNA polymerase (pol ) encounters N⁶-deoxyadenosine adducts formed by trans epoxide ring opening of the 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE) isomer with (+)-7R,8S,9S,10R configuration ((+)-BaP DE-2), misincorporation of A or G and incorporation of the correct T are equally likely to occur. On the other hand, the enzyme exhibits a 3-fold preference for correct T incorporation opposite adducts formed by trans ring opening of the (–)-(7S,8R,9R,10S)-DE-2 enantiomer. Adducts at dA formed by cis ring opening of these two BaP DE-2 isomers exhibit a 2–3-fold preference for A over T incorporation, with G intermediate between the two. Extension one nucleotide beyond these adducts is generally weaker than incorporation across from them, but among mismatches the (adducted A*)·A mispair is the most favored for extension. Because mutations can only occur if mispairs are extended, this observation is consistent with the occurrence of A·T to T·A transversions as common mutations in animal cells treated with BaP DE-2 isomers. Adducts with S absolute configuration at the point of attachment of the hydrocarbon to the base inhibit incorporation and extension by pol to a lesser extent than their R counterparts. Template-primers containing each of the four isomeric dA adducts derived from BaP DE-2 and two adducts derived from 9,10-epoxy-7,8,9,10-tetrahydrobenzo-[a]pyrene in which the 7- and 8-hydroxyl groups of the DEs are replaced with hydrogens exhibit reduced electrophoretic mobilities relative to the unadducted oligonucleotides. This effect is largely independent of DNA sequence. Decreased mobility correlates with an increased rate of incorporation by pol , suggesting a systematic relationship between the overall DNA structure and efficiency of the enzyme.

Received for publication, July 22, 2005 , and in revised form, September 26, 2005.

^* This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains experimental details of the purification and characterization of oligonucleotides in which the nearest-neighbor bases to dA adducts were varied.

¹ To whom correspondence should be addressed: Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892. Tel.: (at American University) 202-885-1772; Fax: 202-885-1752; E-mail: acheh{at}american.edu.

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