TY - JOUR
T1 - Involvement of human MOF in ATM function
AU - Gupta, Arun
AU - Sharma, Girdhar G.
AU - Young, Charles S.H.
AU - Agarwal, Manjula
AU - Smith, Edwin R.
AU - Paull, Tanya T.
AU - Lucchesi, John C.
AU - Khanna, Kum Kum
AU - Ludwig, Thomas
AU - Pandita, Tej K.
PY - 2005/6
Y1 - 2005/6
N2 - 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 ΔhMOF 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.
AB - 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 ΔhMOF 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.
UR - http://www.scopus.com/inward/record.url?scp=20344365811&partnerID=8YFLogxK
U2 - 10.1128/MCB.25.12.5292-5305.2005
DO - 10.1128/MCB.25.12.5292-5305.2005
M3 - Article
C2 - 15923642
AN - SCOPUS:20344365811
SN - 0270-7306
VL - 25
SP - 5292
EP - 5305
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 12
ER -