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Molecular and Cellular Biology, June 2005, p. 5292-5305, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5292-5305.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Involvement of Human MOF in ATM Function

Arun Gupta,1 Girdhar G. Sharma,1 Charles S. H. Young,2 Manjula Agarwal,1 Edwin R. Smith,3,{dagger} Tanya T. Paull,4 John C. Lucchesi,3 Kum Kum Khanna,5 Thomas Ludwig,2 and Tej K. Pandita1*

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108,1 College of Physicians and Surgeons, Columbia University, New York, New York 10032,2 Department of Biology, Emory University, Atlanta, Georgia 30322,3 University of Texas at Austin, Austin, Texas 78712,4 Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia5

Received 22 October 2004/ Returned for modification 13 December 2004/ Accepted 21 March 2005

We have determined that hMOF, the human ortholog of the Drosophila MOF gene (males absent on the first), encoding a protein with histone acetyltransferase activity, interacts with the ATM (ataxia-telangiectasia-mutated) protein. Cellular exposure to ionizing radiation (IR) enhances hMOF-dependent acetylation of its target substrate, lysine 16 (K16) of histone H4 independently of ATM function. Blocking the IR-induced increase in acetylation of histone H4 at K16, either by the expression of a dominant negative mutant {Delta}hMOF or by RNA interference-mediated hMOF knockdown, resulted in decreased ATM autophosphorylation, ATM kinase activity, and the phosphorylation of downstream effectors of ATM and DNA repair while increasing cell killing. In addition, decreased hMOF activity was associated with loss of the cell cycle checkpoint response to DNA double-strand breaks. The overexpression of wild-type hMOF yielded the opposite results, i.e., a modest increase in cell survival and enhanced DNA repair after IR exposure. These results suggest that hMOF influences the function of ATM.

* Corresponding author. Mailing address: Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108. Phone: (314) 747-5461. Fax: (314) 362-9790. E-mail: pandita{at}wustl.edu.

{dagger} Present address: Laboratory of Chromatin Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021.

Molecular and Cellular Biology, June 2005, p. 5292-5305, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5292-5305.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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