Research Interest

Research in my laboratory is focused on the responses of mammalian cells to DNA double-strand breaks (DSBs). DSBs are generated by ionizing radiation and chemotherapeutic agents as well as by the byproducts of cellular metabolism. Cellular responses to DNA damage are of paramount importance in the field of cancer biology because 1) DNA damage causes cancer, 2) DNA damage is used to treat cancer and 3) DNA damage underlies most of the side effects of cancer therapy. My research, therefore, aims to understand some of the mechanisms of DSB recognition, signaling, and repair in mammalian cells. I am particularly interested in the roles of the DNA-dependent Protein Kinase (DNA-PK) and the related kinase, Ataxia Telangiectasia Mutated (ATM), in DNA repair, cell cycle arrest and apoptosis. DNA-PK is a key enzyme in the repair of DSBs in mammalian cells and its deficiency in mice causes radiation sensitivity and cancer predisposition. ATM, which is deficient in the human cancer-predisposition syndrome ataxia telangiectasia, is predominantly involved in enforcing cell cycle checkpoints upon DNA damage. My laboratory is involved in studying responses mounted by DNA-PK and ATM upon DNA damage inflicted by terrestrial radiation (gamma rays) as well as by radiation in outer space (HZE particles). Research projects currently underway in my laboratory focus on the following areas:

1) Role of ATM and DNA-PK in DNA-damage signaling: It is becoming increasingly clear that an inability to mount an appropriate cellular response to DSBs will promote tumorigenesis. We are, thus, currently examining the intricacies of pertinent signaling cascades triggered by ATM or DNA-PK in response to DNA damage. We have identified ATM as the primary kinase that phosphorylates histone H2AX in response to radiation while DNA-PK phosphorylates H2AX late in apoptosis. We have previously demonstrated that though DNA-PK is not required for implementation of cell cycle checkpoints, it is required for the phosphorylation and activation of p53 in cells undergoing apoptosis. Moreover, activation of DNA-PK is attenuated by Gleevac (inhibitor of c-Abl kinase used to treat leukemia); the possible link between c-Abl and DNA-PK in the DNA-damage response is currently being examined. (In collaboration with Dr. David Boothman, Simmons Comprehensive Cancer Center).

2) Molecular basis of radioresistance in glioblastomas: Glioblastomas are brain tumors arising from the glial cells of the brain (astrocytes). These are very aggressive cancers with the poorest prognosis as they are highly radioresistant.  A majority of glioblastomas display amplification of the epidermal growth factor receptor (EGFR). Interestingly, we find that signaling initiated by this receptor impinges on DNA repair processes providing us with a basis for radioresistance and a target for cancer therapy. The mechanistic aspects of the putative link between EGFR and DNA repair in astrocytes, neural stem cells and cancer stem cells are currently being elucidated. (In collaboration with Dr. Robert Bachoo, Dept. of Neuro-oncology)

3) Responses of mammalian cells to Galactic Cosmic Rays: Under the auspices of a $1.2 million, four-year grant from NASA, we are studying the early cellular responses to complex DNA damage inflicted by HZE (High-Z, High-Energy) particles that are the