JBC Transcription and Nuclear Factor Monoclonals

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J Biol Chem, Vol. 275, Issue 6, 3922-3930, February 11, 2000

The Role of Mismatched Nucleotides in Activating the hMSH2-hMSH6 Molecular Switch*

Scott Gradia, Samir Acharya, and Richard FishelDagger

From the Genetics and Molecular Biology Program, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

We have previously shown that hMSH2-hMSH6 contains an intrinsic ATPase which is activated by mismatch-provoked ADPright-arrowATP exchange that coordinately induces the formation of a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone (1, 2). These studies suggested that mismatch repair could be propagated by a signaling event transduced via diffusion of ATP-bound hMSH2-hMSH6 molecular switches to the DNA repair machinery. The Molecular Switch model (Fishel, R. (1998) Genes Dev. 12, 2096-2101) is considerably different than the Hydrolysis-Driven Translocation model (Blackwell, L. J., Martik, D., Bjornson, K. P., Bjornson, E. S., and Modrich, P. (1998) J. Biol. Chem. 273, 32055-32062) and makes additional testable predictions beyond the demonstration of hydrolysis-independent diffusion (Gradia, S., Subramanian, D., Wilson, T., Acharya, S., Makhov, A., Griffith, J., and Fishel, R. (1999) Mol. Cell 3, 255-261): (i) individual mismatch-provoked ADPright-arrowATP exchange should be unique and rate-limiting, and (ii) the kcat·DNA for the DNA-stimulated ATPase activity should decrease with increasing chain length. Here we have examined hMSH2-hMSH6 affinity and ATPase stimulatory activity for several DNA substrates containing mispaired nucleotides as well as the chain length dependence of a defined mismatch under physiological conditions. We find that the results are most consistent with the predictions of the Molecular Switch model.

* This work was supported by National Institutes of Health Grants CA56542 and CA67007.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The biophysical kinetic derivations are dedicated to Robert C. Warner, a continuing inspiration, teacher, and friend.

Dagger To whom correspondence should be addressed: Genetics and Molecular Biology Program, Dept. of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St., Philadelphia, PA 19107. E-mail: rfishel@hendrix.jci.tju.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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