David Johnson, Ph.D.
Present Title & Affiliation
Professor, Department of Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX
- DNA damage response
- Mouse models
- Cell cycle
Two transcription factors respond to DNA damage and play important roles in regulating tumor development.
The first focuses on E2F1, a major regulator of genes important for cell cycle progression and apoptosis. We have discovered that E2F1 also has a non-transcriptional function in stimulating DNA repair in the context of chromatin. We find that E2F1 localizes to sites of both DNA double-strand breaks and UV-induced DNA damage and that this involves the phosphorylation of E2F1 at serine 31 by the ATM or ATR kinases. Our studies indicate that E2F1 promotes efficient DNA repair by recruiting the GCN5 histone acetyltransferase and other chromatin-modifying enzymes to sites of damage to facilitate access to the DNA repair machinery. We have developed a knock-in mouse model that will separate the role of E2F1 in DNA repair from its functions in transcriptionally regulating genes important for cell cycle progression. This mouse model will be used to test the hypothesis that it is the unique ability of E2F1 to respond to DNA damage that underlies its tumor suppressive property.
We also study single nucleotide polymorphism (SNP) in the human p53 gene that results in either an arginine (R) or proline (P) at position 72 of the p53 protein (R72P). This SNP is associated with increased risk for developing a variety of cancers although different variants are associated with risk for different cancers and in some cases there is conflicting data. This polymorphism affects the ability of p53 to induce apoptosis, but the mechanism for this difference is at present unclear. We have developed mouse models that mimic this human SNP and have demonstrated that the humanized p53 variants are functional and display the same differences in apoptotic capacity in mouse tissues as have been observed in human cells. These models are being used to explore the roles of this human SNP in modulating the response to DNA damaging agents and cancer susceptibility.
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