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Involvement of human MOF in ATM function
Arun Gupta1, Girdhar G Sharma, Charles S H Young
1Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, St. Louis, MO 63108, USA.
Molecular and Cellular Biology
|June 1, 2005
Summary
The histone acetyltransferase hMOF interacts with ATM and influences DNA repair. Reduced hMOF impairs ATM activity and DNA double-strand break repair, increasing cell death after radiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The males absent on the first (MOF) gene is conserved across species, with its human ortholog (hMOF) encoding a histone acetyltransferase.
- ATM (ataxia-telangiectasia-mutated) is a key protein kinase involved in DNA damage response.
- Histone modifications play crucial roles in regulating DNA repair pathways.
Purpose of the Study:
- To investigate the functional relationship between hMOF and ATM in response to ionizing radiation (IR).
- To elucidate the role of hMOF-mediated histone acetylation in DNA repair and cell survival.
Main Methods:
- Interaction studies between hMOF and ATM.
- Analysis of histone H4 acetylation at K16 following IR exposure.
- Assessment of ATM autophosphorylation, kinase activity, and downstream effector phosphorylation.
- Evaluation of cell cycle checkpoint response and cell survival after IR.
- Manipulation of hMOF levels using dominant-negative mutants and RNA interference.
Main Results:
- hMOF interacts with ATM.
- Ionizing radiation enhances hMOF-dependent acetylation of histone H4 at K16 independently of ATM.
- Inhibition of hMOF activity reduces ATM activation, DNA repair, and cell cycle checkpoint response, leading to increased cell killing.
- Overexpression of wild-type hMOF enhances cell survival and DNA repair post-IR.
Conclusions:
- hMOF plays a significant role in regulating ATM function and DNA repair.
- hMOF-mediated histone acetylation is critical for the cellular response to DNA double-strand breaks.
- Targeting hMOF activity may represent a strategy for modulating cancer cell radiosensitivity.