Frederick E Domann, Jr, PhD

Associate Professor
Free Radical & Radiation Biology Program
Department of Radiation Oncology

Research Interests

My laboratory focuses on the transcriptional regulation of cancer related genes including oncogenes and tumor suppressor genes. Specifically, we are studying the molecular mechanisms by which aberrant cytosine methylation of CpG dinucleotides affects gene expression during the development of cancer. We have focused primarily on the tumor suppressor gene SOD2 that encodes the antioxidant enzyme superoxide dismutase. We have determined that site specific DNA methylation of the SOD2 gene promoter can suppress its transcriptional activation. Thus, cytosine methylation of genetic regulatory elements within this important tumor suppressor gene can mediate its inactivation. 

We are also studying transcription factor AP-2 and its interactions with the SOD2 promoter. Interestingly, these interactions are affected by DNA methylation. We are also assessing chromatin accessibility in the region of the SOD2 promoter in cells that differentially express the gene. Our future research directions will be aimed at elucidating the role of cytosine methylation as a mechanism for inactivation of other genes involved in protection against oxidative damage as well as other classical tumor suppressor genes, and to elucidate the mechanism(s) by which CpG methylation can bring about these changes in gene expression.

We have recently been studying mechanisms underlying the transcriptional silencing of another tumor suppressor gene called maspin. We have determined that this gene is transcriptionally silenced in the majority of advanced human breast cancers by an epigenetic mechanism involving aberrant cytosine methylation and chromatin condensation of its promoter. We are continuing to investigate the mechanisms that contribute to transcriptional regulation of this gene in human cancer.

Our newest avenue of investigation is the pre-clinical development of a novel form of genetically targeted radiotherapy for head and neck cancer.  Using gene delivery of the sodium iodide symporter gene, we have shown that the phenotype of iodide accumulation can be conferred on tumor cells thus allowing them to be destroyed by systemically administered cytotoxic radioiodine isotopes.  These pre-clinical studies are paving the way to clinical trials using genetically targeted radiotherapy.  In addition to its therapeutic applications, the symporter is also being used in imaging applications to track gene delivery and expression by non-invasive radiological means.