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.
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.
|Gupta, Arun; Hunt, Clayton R; Chakraborty, Sharmistha et al. (2014) Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res 181:1-8|
|Pushpavalli, Sreerangam N C V L; Sarkar, Arpita; Bag, Indira et al. (2014) Argonaute-1 functions as a mitotic regulator by controlling Cyclin B during Drosophila early embryogenesis. FASEB J 28:655-66|
|Bolderson, Emma; Petermann, Eva; Croft, Laura et al. (2014) Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks. Nucleic Acids Res 42:6326-36|
|Gupta, Arun; Hunt, Clayton R; Hegde, Muralidhar L et al. (2014) MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. Cell Rep 8:177-89|
|Yadav, Vinod Kumar; Thakur, Ram Krishna; Eckloff, Bruce et al. (2014) Promoter-proximal transcription factor binding is transcriptionally active when coupled with nucleosome repositioning in immediate vicinity. Nucleic Acids Res 42:9602-11|
|Pandita, Tej K (2014) Unraveling the novel function of the DNA repair enzyme 8-oxoguanine-DNA glycosylase in activating key signaling pathways. Free Radic Biol Med 73:439-40|
|Sun, Chong-kui; Zhang, Fan; Xiang, Tao et al. (2014) Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers. Oncotarget 5:3375-85|
|Provenzano, P P; Hingorani, S R (2013) Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer 108:1-8|
|Singh, Mayank; Hunt, Clayton R; Pandita, Raj K et al. (2013) Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol 33:1210-22|
|Gupta, Arun; Hunt, Clayton R; Pandita, Raj K et al. (2013) T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice. Mutagenesis 28:263-70|
Showing the most recent 10 out of 24 publications