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PMID: 15923642 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Involvement of human MOF in ATM function.

Molecular and cellular biology ·Vol. 25 ·No. 12 ·2005-06-00 ·Pages 5292-305

Gupta A, Sharma GG, Young CS, Agarwal M, Smith ER, Paull TT, Lucchesi JC, Khanna KK, Ludwig T, Pandita TK

Abstract

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 DeltahMOF 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.

MeSH Terms
Acetyltransferases/genetics,metabolism Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/genetics,metabolism Cell Line Cell Survival Chromosome Aberrations DNA/metabolism,radiation effects DNA Damage DNA Repair DNA-Binding Proteins/genetics,metabolism Drosophila melanogaster Genomic Instability Histone Acetyltransferases Histones/metabolism Humans Male Phosphorylation Protein Binding Protein Serine-Threonine Kinases/genetics,metabolism Radiation, Ionizing Tumor Suppressor Proteins/genetics,metabolism Two-Hybrid System Techniques
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Histones Tumor Suppressor Proteins DNA Acetyltransferases Histone Acetyltransferases KAT8 protein, human ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Gupta Arun
Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108, USA.
Sharma Girdhar G
Young Charles S H
Agarwal Manjula
Smith Edwin R
Paull Tanya T
Lucchesi John C
Khanna Kum Kum
Ludwig Thomas
Pandita Tej K
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.12.5292-5305.2005
Published
2005-06-00
Pages
5292-305
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1140595
Subset
IM
Grants
NCI NIH HHS · P01 CA097403 · United States
NCI NIH HHS · CA10445 · United States
NINDS NIH HHS · NS34746 · United States
NINDS NIH HHS · R01 NS034746 · United States
NCI NIH HHS · P01 CA97403 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.12.5292-5305.2005 PMC Full Text View journal details
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