The effect of DNA mismatches on the ATPase activity of MSH1, a protein in yeast mitochondria that recognizes DNA mismatches.

MSH1 is a DNA-binding protein in yeast mitochondria that recognizes nucleotide mismatches in DNA and plays a role in mitochondrial mutation avoidance (Chi, W., and Kolodner, R. D. (1994) J. Biol. Chem. 269, 29984-29992). MSH1 exhibits an ATPase activity that hydrolyses approximately 1 ATP molecule/min in the absence of DNA. In this study, p3 show that DNA alters the pH dependence of the MSH1 ATPase and stimulates ATP hydrolysis at neutral pH. Using heteroduplex DNA containing mismatches with various affinity, we show an inverse correlation between the extent of ATPase stimulation by DNA and the binding affinity of MSH1 for the DNA effector. We also show that the presence of ATP increases the mismatch specificity of MSH1-DNA binding. Taken together, the observed interaction between the ATPase and the mismatch-binding activities suggests that MSH1 binds to ATP and mismatches with positive cooperativity. This interaction may provide a system for elucidating the role of ATP in mismatch recognition and repair.