HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 48, 50280-50285, November 26, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/48/50280    most recent M409224200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hsu, G. W. Articles by Beese, L. S. Search for Related Content PubMed PubMed Citation Articles by Hsu, G. W. Articles by Beese, L. S. Social Bookmarking                      What's this?

Observing Translesion Synthesis of an Aromatic Amine DNA Adduct by a High-fidelity DNA Polymerase^*

Gerald W. Hsu, James R. Kiefer, Dominique Burnouf¶, Olivier J. Becherel¶||, Robert P. P. Fuchs¶, and Lorena S. Beese**

From the Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 and ^¶Cancerogenese et Mutagenese Moleculaire et Structurale, Unité Propre de Recherche 9003 du Centre National de la Recherche Scientifique, 67400 Strasbourg, France

Aromatic amines have been studied for more than a half-century as model carcinogens representing a class of chemicals that form bulky adducts to the C8 position of guanine in DNA. Among these guanine adducts, the N-(2'-deoxyguanosin-8-yl)-aminofluorene (G-AF) and N-2-(2'-deoxyguanosin-8-yl)-acetylaminofluorene (G-AAF) derivatives are the best studied. Although G-AF and G-AAF differ by only an acetyl group, they exert different effects on DNA replication by replicative and high-fidelity DNA polymerases. Translesion synthesis of G-AF is achieved with high-fidelity polymerases, whereas replication of G-AAF requires specialized bypass polymerases. Here we have presented structures of G-AF as it undergoes one round of accurate replication by a high-fidelity DNA polymerase. Nucleotide incorporation opposite G-AF is achieved in solution and in the crystal, revealing how the polymerase accommodates and replicates past G-AF, but not G-AAF. Like an unmodified guanine, G-AF adopts a conformation that allows it to form Watson-Crick hydrogen bonds with an opposing cytosine that results in protrusion of the bulky fluorene moiety into the major groove. Although incorporation opposite G-AF is observed, the C:G-AF base pair induces distortions to the polymerase active site that slow translesion synthesis.

Received for publication, August 11, 2004 , and in revised form, September 20, 2004.

The atomic coordinates and structure factors (codes 1UA0 and 1UA1) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Human Frontiers Science Program Grants RG0351/1998-M (to R. P. P. F. and L. S. B.) and NCI, National Institues of Health Grant PO1 CA92584 (to L. S. B.). 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.

Present address: Pfizer Inc., St. Louis, MO 63198.

^|| Present address: Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, The Bancroft Centre, Royal Brisbane Hospital Post Office, Brisbane 4029, Queensland, Australia.

^** To whom correspondence should be addressed: Dept. of Biochemistry, Box 3711, Duke University Medical Center, Durham, NC 27710. Tel.: 919-681-5267; Fax: 919-684-8885; E-mail: lsb{at}biochem.duke.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. Xu, L. Oum, L. S. Beese, N. E. Geacintov, and S. Broyde Following an environmental carcinogen N2-dG adduct through replication: elucidating blockage and bypass in a high-fidelity DNA polymerase Nucleic Acids Res., July 26, 2007; 35(13): 4275 - 4288. [Abstract] [Full Text] [PDF]

				J. J. Warren, L. J. Forsberg, and L. S. Beese The structural basis for the mutagenicity of O6-methyl-guanine lesions PNAS, December 26, 2006; 103(52): 19701 - 19706. [Abstract] [Full Text] [PDF]

				J.-Y. Choi, J. S. Stover, K. C. Angel, G. Chowdhury, C. J. Rizzo, and F. P. Guengerich Biochemical Basis of Genotoxicity of Heterocyclic Arylamine Food Mutagens: HUMAN DNA POLYMERASE {eta} SELECTIVELY PRODUCES A TWO-BASE DELETION IN COPYING THE N2-GUANYL ADDUCT OF 2-AMINO-3-METHYLIMIDAZO[4,5-f]QUINOLINE BUT NOT THE C8 ADDUCT AT THE NarI G3 SITE J. Biol. Chem., September 1, 2006; 281(35): 25297 - 25306. [Abstract] [Full Text] [PDF]

				L. Wang and S. Broyde A new anti conformation for N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (AAF-dG) allows Watson-Crick pairing in the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) Nucleic Acids Res., February 1, 2006; 34(3): 785 - 795. [Abstract] [Full Text] [PDF]

				S. R. Meneni, R. D'Mello, G. Norigian, G. Baker, L. Gao, M. P. Chiarelli, and B. P. Cho Sequence effects of aminofluorene-modified DNA duplexes: thermodynamic and circular dichroism properties Nucleic Acids Res., January 30, 2006; 34(2): 755 - 763. [Abstract] [Full Text] [PDF]

				G. W. Hsu, X. Huang, N. P. Luneva, N. E. Geacintov, and L. S. Beese Structure of a High Fidelity DNA Polymerase Bound to a Benzo[a]pyrene Adduct That Blocks Replication J. Biol. Chem., February 4, 2005; 280(5): 3764 - 3770. [Abstract] [Full Text] [PDF]