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Papers In Press, published online ahead of print July 31, 2002
Biochem and Molec Biology, LSU Health Sciences Center, New Orleans, LA 70112
Corresponding Author: kbrown1{at}lsuhsc.edu
p53 plays an important role in response to ionizing radiation (IR) by regulating cell cycle progression and triggering apoptosis. These activities are controlled, in part, by the phosphorylation of p53 by the protein kinase ATM. Recent evidence indicates the monofunctional DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) also triggers upregulation and phosphorylation of p53; however, the mechanism(s) responsible for this are unknown. We observed that, in MNNG-treated normal human fibroblasts (NHF), upregulation and phosphorylation of p53 was sensitive to the ATM kinase inhibitor wortmannin. ATM-deficient fibroblasts exhibited a delay in p53 upregulation indicating a role for ATM in triggering the MNNG-induced response. Likewise, a mismatch repair (MMR)-deficient colorectal tumor line failed to show rapid upregulation of p53. However, unlike ATM-deficient cells, these MMR-deficient cells displayed rapid phosphorylation of the p53 residue serine 15 after MNNG. In vitro kinase assays indicate that ATM is rapidly activated in both normal and MMR-deficient cells in response to MNNG. Using a number of morphological and biochemical approaches, we failed to observe MNNG-induced apoptosis in NHF, suggesting that apoptosis-induced DNA strand breaks are not required for the activation of ATM in response to MNNG. Comet assays indicated that strand breaks accumulated, and p53 upregulation/phosphorylation occurred quite rapidly (within 30 min) after MNNG treatment, suggesting that DNA strand breaks which arise during the repair process activate ATM. These findings indicate that ATM activation is not limited to the IR-induced response and potentially plays an important role in response to DNA alkylation.
J. Biol. Chem, 10.1074/jbc.M204409200
Submitted on May 6, 2002
Revised on July 23, 2002
Accepted on July 31, 2002
ATM is activated in response to MNNG-induced DNA alkylation
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