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J. Biol. Chem., Vol. 278, Issue 23, 21267-21275, June 6, 2003

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Binding Discrimination of MutS to a Set of Lesions and Compound Lesions (Base Damage and Mismatch) Reveals Its Potential Role as a Cisplatin-damaged DNA Sensing Protein^*

Laurence Fourrier , Peter Brooks  ¶ and Jean-Marc Malinge ||

From the Centre de Biophysique Moléculaire, CNRS, Rue Charles Sadron, 45071 Orléans Cedex 02, France, Génoscope-Centre National de Séquençage, 2, rue Gaston Crémieux CP 5706, 91057 Evry Cedex, France

The DNA mismatch repair (MMR) system plays a critical role in sensitizing both prokaryotic and eukaryotic cells to the clinically potent anticancer drug cisplatin. It is thought to mediate cytotoxicity through recognition of cisplatin DNA lesions. This drug generates a range of lesions that may also give rise to compound lesions resulting from the misincorporation of a base during translesion synthesis. Using gel mobility shift competition assays and surface plasmon resonance, we have analyzed the interaction of Escherichia coli MutS protein with site-specifically modified DNA oligonucleotides containing each of the four cisplatin cross-links or a set of compound lesions. The major 1,2-d(GpG) cisplatin intrastrand cross-link was recognized with only a 1.5-fold specificity, whereas a 47-fold specificity was found with a natural G/T containing DNA substrate. The rate of association, k_on, for binding to the 1,2-d(GpG) adduct was 3.1 x 10⁴ M-1 s^-1 and the specificity of binding was essentially dependent on k_off. DNA duplexes containing a single 1,2-d(ApG), 1,3-d(GpCpG) adduct, and an interstrand cross-link of cisplatin were not preferentially recognized. Among 12 DNA substrates, each containing a different cisplatin compound lesion derived from replicative misincorporation of one base opposite either of the 1,2-intrastrand adducts, 10 were specifically recognized including those that are more likely formed in vivo based on cisplatin mutation spectra. Moreover, among these lesions, two compound lesions formed when an adenine was misincorporated opposite a 1,2-d(GpG) adduct were not substrates for the MutY-dependent mismatch repair pathway. The ability of MutS to sense differentially various platinated DNA substrates suggests that cisplatin compound lesions formed during misincorporation of a base opposite either adducted base of both 1,2-intrastrand cross-links are more plausible critical lesions for MMR-mediated cisplatin cytotoxicity.

Received for publication, February 7, 2003 , and in revised form, March 20, 2003.

^* This work was supported in part by the Ligue contre le Cancer, Association pour la Recherche sur le Cancer, and COST Chemistry Actions D20. 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.

Supported by a grant from the Ministère de l'Enseignement Supérieur et de la Recherche.

^¶ On leave at Genoscope from the Centre National de la Recherche Scientifique. Present address: IntegraGen, 4, rue Pierre Fontaine, 91000 Evry, France.

^|| To whom correspondence should be addressed. Tel.: 33-2-38-25-55-44; Fax: 33-2-38-63-15-17; E-mail: malinge{at}cnrs-orleans.fr.

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