In eukaryotic cells, ionizing radiation (IR) induced DNA damage activates signal transduction pathways that rapidly affect downstream processes such as gene transcription, cell-cycle progression and DNA replication. All of these processes require chromatin alterations to allow for DNA access. For several years we have been studying the role of the ATM (mutated in ataxia-telangiectasia) in DNA damage repair and maintenance of telomere chromatin structure. Cells deficient in ATM have defects in DNA repair and display altered telomere chromatin structure. Recently, we have identified a chromatin-modifying factor "hMOF" the human ortholog of Drosophila MOF gene (males absent on the first) that is essential for early embryonic survival in mice. hMOF has a chromodomain and histone acetyltransferase (HAT) activity that interacts with ATM. Cellular exposure to IR enhances hMOF-dependent acetylation of its target substrate, lysine 16 (K16) of histone H4, independent of ATM function. However, inactivation of hMOF results in abrogation of ATM autophosphorylation, ATM kinase activity and DNA repair while increasing cell killing after IR exposure. Based on these preliminary studies, that hMOF participates in the IR-dependent activation of ATM, we hypothesize that hMOF has multiple roles in addition to being involved in the regulation of DNA damage-induced ATM activation. In the proposed work, we will determine ATM independent role of hMOF in IR response for cell survival, DNA DSB repair and telomere metabolism. Experiments described in this proposal will investigate the functional links between hMOF and IR response. We will investigate mechanisms by which hMOF influences genomic instability. These studies will improve our understanding of the role of hMOF in telomere chromatin structure, DNA DSB repair and, ATM independent role of the MOF in IR response. Ultimately, understanding the links between hMOF and ATM could provide strategies for modifying the response to IR that could be useful in clinical radiation therapy, since tumor cells and normal cells have significant differences in their chromatin structure and telomere metabolism.

Public Health Relevance

This project will define the role of hMOF in the cellular response to ionizing radiation, telomere metabolism and DNA repair. The results of the proposed studies will further our understanding of how hMOF is involved in recognizing, signaling and repairing double-strand breaks. In addition this study will provide the mechanistic basis for understanding how the chromatin barrier to DNA access is regulated by hMOF activity to ensure telomere maintenance and repair of DNA DSBs. Thus understanding these mechanisms is critical to both cancer prevention as well as development of strategies to optimize targeted and combinatorial treatment regimens with regard to the disease Ataxia- Telangiectasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129537-06
Application #
8305606
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$320,027
Indirect Cost
$118,752
Name
University of Texas Sw Medical Center Dallas
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mujoo, Kalpana; Butler, E Brian; Pandita, Raj K et al. (2016) Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations. Radiat Res 186:17-26
Horikoshi, Nobuo; Pandita, Raj K; Mujoo, Kalpana et al. (2016) β2-spectrin depletion impairs DNA damage repair. Oncotarget 7:33557-70
Sadik, Helen; Korangath, Preethi; Nguyen, Nguyen K et al. (2016) HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells. Cancer Res 76:4443-56
Deb, Paromita; Bhan, Arunoday; Hussain, Imran et al. (2016) Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo. Gene 590:234-43
Farooq, Zeenat; Banday, Shahid; Pandita, Tej K et al. (2016) The many faces of histone H3K79 methylation. Mutat Res Rev Mutat Res 768:46-52
Mujoo, Kalpana; Hunt, Clayton R; Horikoshi, Nobuo et al. (2016) A multifaceted role for MOF histone modifying factor in genome maintenance. Mech Ageing Dev :
Udayakumar, Durga; Pandita, Raj K; Horikoshi, Nobuo et al. (2016) Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair. Radiat Res 185:527-38
Chakraborty, Anirban; Tapryal, Nisha; Venkova, Tatiana et al. (2016) Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes. Nat Commun 7:13049
Gaur, Puja; Hunt, Clayton R; Pandita, Tej K (2016) Emerging therapeutic targets in esophageal adenocarcinoma. Oncotarget :
Jacquet, Karine; Fradet-Turcotte, Amélie; Avvakumov, Nikita et al. (2016) The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation. Mol Cell 62:409-21

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