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Molecular and Cellular Biology, February 2009, p. 907-918, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00945-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Characterization of a Highly Conserved Binding Site of Mlh1 Required for Exonuclease I-Dependent Mismatch Repair ^,

Claudine Dherin,^1,2, Emeric Gueneau,^3,4, Mathilde Francin,^1,2, Marcela Nunez,^3,4 Simona Miron,^5,6 Sascha Emilie Liberti,⁷ Lene Juel Rasmussen,⁷ Sophie Zinn-Justin,^3,4 Bernard Gilquin,^3,4 Jean-Baptiste Charbonnier,^3,4* and Serge Boiteux^1,2*

CEA, IRCM, UMR217, Radiobiologie Moléculaire et Cellulaire, F-92265 Fontenay aux Roses, France,¹ CNRS, UMR217, F-92265 Fontenay aux Roses, France,² CEA, IBITECS, Laboratoire de Biologie Structurale et Radiobiologie, CE-Saclay, F-91191 Gif sur Yvette, France,³ CNRS, URA 2096, F-91191 Gif sur Yvette, France,⁴ Institut Curie, Centre de Recherche, Université Paris-Sud, Bât 112, Orsay 91405, France,⁵ INSERM, U759, Orsay 91405, France,⁶ Department of Science Systems and Models, Roskilde University, 4000 Roskilde, Denmark⁷

Received 13 June 2008/ Returned for modification 15 July 2008/ Accepted 2 November 2008

Mlh1 is an essential factor of mismatch repair (MMR) and meiotic recombination. It interacts through its C-terminal region with MutL homologs and proteins involved in DNA repair and replication. In this study, we identified the site of yeast Mlh1 critical for the interaction with Exo1, Ntg2, and Sgs1 proteins, designated as site S2 by reference to the Mlh1/Pms1 heterodimerization site S1. We show that site S2 is also involved in the interaction between human MLH1 and EXO1 or BLM. Binding at this site involves a common motif on Mlh1 partners that we called the MIP-box for the Mlh1 interacting protein box. Direct and specific interactions between yeast Mlh1 and peptides derived from Exo1, Ntg2, and Sgs1 and between human MLH1 and peptide derived from EXO1 and BLM were measured with K_d values ranging from 8.1 to 17.4 µM. In Saccharomyces cerevisiae, a mutant of Mlh1 targeted at site S2 (Mlh1-E682A) behaves as a hypomorphic form of Exo1. The site S2 in Mlh1 mediates Exo1 recruitment in order to optimize MMR-dependent mutation avoidance. Given the conservation of Mlh1 and Exo1 interaction, it may readily impact Mlh1-dependent functions such as cancer prevention in higher eukaryotes.

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* Corresponding author. Mailing address for Serge Boiteux: CEA, IRCM, UMR217, Radiobiologie Moléculaire et Cellulaire, F-92265 Fontenay aux Roses, France. Phone: 33 1 46 54 88 58. Fax: 33 1 46 54 88 59. E-mail: serge.boiteux{at}cea.fr. Mailing address for Jean-Baptiste Charbonnier: CEA, IBITECS, CE-Saclay, Bât 144, F-91191 Gif sur Yvette, France. Phone: 33 1 69 08 76 77. Fax: 33 1 69 08 47 12. E-mail: jb.charbonnier{at}cea.fr

Published ahead of print on 17 November 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

C.D. and E.G. contributed equally to this study.

Present address: INRA de Nantes, Unité BIA, Rue de la Géraudière, BP71627, 44316 Nantes, Cedex 03, France.

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Molecular and Cellular Biology, February 2009, p. 907-918, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00945-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.