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Nucleic Acids Research 2005 33(4):1410-1419; doi:10.1093/nar/gki291
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Published online 3 March 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2–MSH6 complex

Sreeparna Banerjee1 and Hernan Flores-Rozas1,2,*

1Institute of Molecular Medicine and Genetics, Medical College of Georgia 1120 15th Street, Augusta GA 30912, USA 2Department of Medicine, Medical College of Georgia 1120 15th Street, Augusta GA 30912, USA

*To whom correspondence should be addressed at Medical College of Georgia, 1120 15th Street, CB-2803, Augusta, GA 30912, USA. Tel: +1 706 721 1371; Fax: +1 706 721 8752; Email: hfloresrozas{at}mail.mcg.edu

Received November 18, 2004. Revised February 18, 2005. Accepted February 18, 2005.

Cadmium (Cd2+) is a known carcinogen that inactivates the DNA mismatch repair (MMR) pathway. In this study, we have tested the effect of Cd2+ exposure on the enzymatic activity of the mismatch binding complex MSH2–MSH6. Our results indicate that Cd2+ is highly inhibitory to the ATP binding and hydrolysis activities of MSH2–MSH6, and less inhibitory to its DNA mismatch binding activity. The inhibition of the ATPase activity appears to be dose and exposure time dependent. However, the inhibition of the ATPase activity by Cd2+ is prevented by cysteine and histidine, suggesting that these residues are essential for the ATPase activity and are targeted by Cd2+. A comparison of the mechanism of inhibition with N-ethyl maleimide, a sulfhydryl group inhibitor, indicates that this inhibition does not occur through direct inactivation of sulfhydryl groups. Zinc (Zn2+) does not overcome the direct inhibitory effect of Cd2+ on the MSH2–MSH6 ATPase activity in vitro. However, the increase in the mutator phenotype of yeast cells exposed to Cd2+ was prevented by excess Zn2+, probably by blocking the entry of Cd2+ into the cell. We conclude that the inhibition of MMR by Cd2+ is through the inactivation of the ATPase activity of the MSH2–MSH6 heterodimer, resulting in a dominant negative effect and causing a mutator phenotype.


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