The heavy metal cadmium (Cd) is a human carcinogen that inhibits DNA repairs activities. We show that DNA mismatch repair (MMR)-mediated cell cycle arrest after alkylation damage is suppressed by exposure to Cd and that this effect is reserved by preincubation with excess of zinc (Zn). We show that Cd-mediated inactivation of MMr activity is not caused by disruption of complex formation between the MMR proteins hEXO1-hMutSalpha and hEXO1-hMutSalpha nor does Cd inhibit 5'-exonuclease activity of hEXO1 in vitro. Thus, our studies show that exposure of human cells to Cd suppresses MMR activity, a repair known to play an important role in colon cancer and that this effect can be reversed by Zn treatment. (C) 2004 Elsevier Inc. All rights reserved.