The E2F1 transcription factor regulates the expression of genes involved in cell cycle progression, apoptosis and differentiation. More recent findings, including our preliminary data, indicate that E2F1 has additional functions in DNA repair that are independent of transcription. E2F1 is found to accumulate at sites of DNA double-strand breaks as well as UV radiation-induced DNA damage. Localization of E2F1 to damaged DNA requires the phosphorylation of E2F1 on serine 31 by the ATM or ATR kinases and subsequent binding to the TopBP1 protein. At present, the function of E2F1 at sites of DNA damage is unclear and the goal of this proposal is to fill this gap in knowledge. The overall hypothesis of this application is that E2F1 participates in the recruitment of chromatin modifying enzymes and DNA repair factors to sites of damage to directly enhance some forms of DNA repair.
Specific Aim 1 is to determine the mechanism by which E2F1 stimulates nucleotide excision repair of UV-induced damage while Specific Aim 2 is to determine the role of E2F1 in DNA double-strand break repair.
Specific Aim 3 is to determine the physiological relevance of E2F1 in the DNA damage response using a newly developed E2F1 serine 31 mutant knock-in mouse model. Together, these studies will establish new functions for E2F1 in the DNA damage response and reveal novel mechanisms to enhance DNA repair that operate at the level of chromatin structure. These studies are highly significant for understanding the cellular response to many cancer causing agents and well as the response to conventional cancer therapies.
Some DNA damaging agents cause cancer while others are used to treat cancer. Thus, studying the cellular response to DNA damage is crucial for understanding cancer development and the response to therapy. This proposal will study the role of the E2F1 protein in the response to DNA damage, particularly a novel function at sites of damage that directly enhances DNA repair.
|Biswas, Anup Kumar; Mitchell, David L; Johnson, David G (2014) E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis. Cancer Res 74:3369-77|
|Johnson, David G; Dent, Sharon Y R (2013) Chromatin: receiver and quarterback for cellular signals. Cell 152:685-9|
|Biswas, Anup K; Johnson, David G (2012) Transcriptional and nontranscriptional functions of E2F1 in response to DNA damage. Cancer Res 72:13-7|
|Velez-Cruz, Renier; Johnson, David G (2012) E2F1 and p53 Transcription Factors as Accessory Factors for Nucleotide Excision Repair. Int J Mol Sci 13:13554-68|
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|Pusapati, Raju V; Weaks, Regina L; Rounbehler, Robert J et al. (2010) E2F2 suppresses Myc-induced proliferation and tumorigenesis. Mol Carcinog 49:152-6|
|Guo, Ruifeng; Chen, Jie; Zhu, Feng et al. (2010) E2F1 localizes to sites of UV-induced DNA damage to enhance nucleotide excision repair. J Biol Chem 285:19308-15|
|Paulson, Q X; Pusapati, R V; Hong, S et al. (2008) Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis. Oncogene 27:4954-61|
|Hong, Sungki; Paulson, Qiwei X; Johnson, David G (2008) E2F1 and E2F3 activate ATM through distinct mechanisms to promote E1A-induced apoptosis. Cell Cycle 7:391-400|
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