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Purified Human MSH2 Protein Binds to DNA Containing Mismatched Nucleotides¹

Department of Microbiology and Molecular Genetics, Markey Center for Molecular Genetics, University of Vermont School of Medicine, Burlington, Vermont 05405

The human hMSH2 protein is a member of a highly conserved family of postreplication mismatch repair components found from bacteria to humans. Alterations of the gene coding for this protein cosegregate with, and are the likely cause of, chromosome 2-linked hereditary nonpolyposis colon cancer. Postreplication mismatch repair has been found to faithfully replace misincorporated nucleotides, thereby increasing the overall fidelity of DNA replication. Loss of postreplication mismatch repair function leads to a mutator phenotype, which is proposed to account for the multiple mutations required for multistep carcinogenesis. Although the functions of hMSH2 can be anticipated based on its similarity to well-characterized bacterial and yeast proteins, proof of its functions has not been established. Here we demonstrate that purified hMSH2 binds specifically to mismatched nucleotides, providing a target for the excision repair processes characteristic of postreplication mismatch repair.

¹ This work was supported by NIH Grant CA 56542 and the Lake Champlain Cancer Research Organization.

² To whom requests for reprints should be addressed, at Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Stafford Hall, Burlington, VT 05405-0068.

Received 9/13/94. Accepted 9/19/94.

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