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J. Biol. Chem., Vol. 279, Issue 9, 7947-7955, February 27, 2004

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Position-specific Suppression and Enhancement of HIV-1 Integrase Reactions by Minor Groove Benzo[a]pyrene Diol Epoxide Deoxyguanine Adducts

IMPLICATIONS FOR MOLECULAR INTERACTIONS BETWEEN INTEGRASE AND DNA SUBSTRATES^*

Allison A. Johnson, Jane M. Sayer, Haruhiko Yagi, Govind P. Kalena, Ronak Amin, Donald M. Jerina, and Yves Pommier¶

From the Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

The viral protein HIV-1 integrase is required for insertion of the viral genome into human chromosomes and for viral replication. Integration proceeds in two consecutive integrase-mediated reactions: 3'-processing and strand transfer. To investigate the DNA minor groove interactions of integrase relative to known sites of integrase action, we synthesized oligodeoxynucleotides containing single covalent adducts of known absolute configuration derived from trans-opening of benzo-[a]pyrene 7,8-diol 9,10-epoxide by the exocyclic 2-amino group of deoxyguanosine at specific positions in a duplex sequence corresponding to the terminus of the viral U5 DNA. Because the orientations of the hydrocarbon in the minor groove are known from NMR solution structures of duplex oligonucleotides containing these deoxyguanosine adducts, a detailed analysis of the relationship between the position of minor groove ligands and integrase interactions is possible. Adducts placed in the DNA minor groove two or three nucleotides from the 3'-processing site inhibited both 3'-processing and strand transfer. Inosine substitution showed that the guanine 2-amino group is required for efficient 3'-processing at one of these positions and for efficient strand transfer at the other. Mapping of the integration sites on both strands of the DNA substrates indicated that the adducts both inhibit strand transfer specifically at the minor groove bound sites and enhance integration at sites up to six nucleotides away from the adducts. These experiments demonstrate the importance of positionspecific minor groove contacts for both the integrase-mediated 3'-processing and strand transfer reactions.

Received for publication, October 13, 2003 , and in revised form, November 18, 2003.

^* 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 Table IS and Fig. 1S.

^¶ To whom correspondence should be addressed: Laboratory of Molecular Pharmacology, Building 37, Room 5068, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-5944; Fax: 301-402-0752; E-mail: pommier{at}nih.gov.

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