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

Oxford University Press
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gki291 1410..1419 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 and 2Department of Medicine, Medical College of Georgia, 1120 15th Street, Augusta GA 30912, USA Received November 18, 2004; Revised and Accepted February 18, 2005 ABSTRACT Cadmium (Cd21) is a known carcinogen that inactiv- ates the DNA mismatch repair (MMR) pathway. In this study, we have tested the effect of Cd21 exposure on the enzymatic activity of the mismatch binding com- plex MSH2–MSH6. Our results indicate that Cd21 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 expo- sure time dependent. However, the inhibition of the ATPase activity by Cd21 is prevented by cysteine and histidine, suggesting that these residues are essential for the ATPase activity and are targeted by Cd21. 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 (Zn21) does not overcome the direct inhibitory effect of Cd21 on the MSH2–MSH6 ATPase activity in vitro. However, the increase in the mutator phenotype of yeast cells exposed to Cd21 was prevented by excess Zn21, prob- ably by blocking the entry of Cd21 into the cell. We conclude that the inhibition of MMR by Cd21 is through the inactivation of the ATPase activity of the MSH2–MSH6 heterodimer, resulting in a dominant negative effect and causing a mutator phenotype. INTRODUCTION Mispaired bases result from incorporation errors during DNA biosynthesis that have escaped the proofreading activity of DNA polymerases as well as from the formation of hetero- duplex DNA during recombination of divergent sequences. DNA mismatch repair (MMR) plays a major role in the r

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