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RESEARCH COMMUNICATION
1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA; 2 The Burnham Institute, La Jolla, California 92037, USA; 3 Department of Functional Genomics, GeneTrove (A Division of Isis Pharmaceuticals), Carlsbad, California 92008, USA
The checkpoint kinase ATM is centrally involved in the cellular response to DNA double-strand breaks. However, the mechanism of ATM activation during genotoxicstress is only partially understood. Here we report a direct regulatory linkage between the protein serine-threonine phosphatase 5 (PP5) and ATM. PP5 interacts with ATM in a DNA-damage-inducible manner. Reduced expression of PP5 attenuated DNA-damage-induced activation of ATM. Expression of a catalytically inactive PP5 mutant inhibited the phosphorylation of ATM substrates and the autophosphorylation of ATM on Ser 1981, and caused an S-phase checkpoint defect in DNA-damaged cells. Together our findings indicate that PP5 plays an essential role in the activation and checkpoint signaling functions of ATM in cells that have suffered DNA double-strand breaks.
[Keywords: DNA damage; cell cycle checkpoint; ATM; protein phosphatase 5]
Received December 2, 2003; revised version accepted December 22, 2003.
Supplemental material is available at http://www.genesdev.org.
4 These authors contributed equally to this work.
5 Corresponding author.
E-MAIL wang0011{at}mc.duke.edu; FAX (919) 681-7152.
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