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 most deleterious component of Galactic Cosmic Rays. We are particularly interested in the biological effects of HZE particles that have interacted with the shielding materials of spacecrafts and space stations as these materials can either ameliorate or exacerbate the effects of these ions. Our studies should eventually provide us with biological endpoints for the estimation of cancer risks to astronauts and for the design of better futuristic space shielding. These studies are also pertinent from a therapeutic standpoint due to the increasing use of protons and carbon ions in targeted cancer therapy. (In collaboration with Dr. Jack Miller, Lawrence Berkeley National Laboratory)
RESEARCH INTERESTS
Recognition, signaling, and repair of DNA double-strand breaks
The DNA damage response as a barrier to carcinogenesis
Induction of cell cycle arrest or apoptosis by ATM or DNA-PK
Molecular basis of radioresistance in glioblastomas
Responses of mammalian cells to Galactic Cosmic Rays
RECENT PUBLICATIONS
N Tomimatsu, GG Tahimic, A Otsuki, S Burma, A Fukuhara, K Sato, G Shiota, M Oshimura, DJ Chen, A Kurimasa, "Ku70/80 modulates ATM and ATR signaling pathways in response to DNA double-strand breaks." J Biol Chem, 282(14):10138-45, April 2007
J Li, DP Sejas, S Burma, DJ Chen, Q Pang, "Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability." Carcinogenesis, 28(6):1163-70, June 2007
Mukherjee B, Kessinger C, Kobayashi J, Chen BP, Chen DJ, Chatterjee A, Burma S, "DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells." DNA Repair, 5(5):575-590, May 2006
Chen BP, Chan DW, Kobayashi J, Burma S, Asaithamby A, Morotomi-Yano K, Botvinick E, Qin J, Chen DJ, "Cell cycle dependence of DNA-PK phosphorylation in response to DNA double-strand breaks." J Biol Chem., 280(15):14709-15, April 2005
Silvera D, Koloteva-Levine N, Burma S, Elroy-Stein O, "Effect of Ku proteins on IRES-mediated translation." Biol Cell, 98(6):353-61, June 2006
SIGNIFICANT PUBLICATIONS
Burma S, Chen B, Chen DJ, "Role of non-homologous end joining (NHEJ) in maintaining genomic integrity." DNA Repair, 5(9-10):1042-48, September 2006
Burma S, Chen DJ, "Role of DNA-PK in the cellular response to DNA double-strand breaks." DNA Repair, 3(8-9):909-18, August 2004
Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ, "ATM phosphorylates histone H2AX in response to DNA double-strand breaks." J Biol Chem., 276(45):42462-7, November 2001
Burma S, Kurimasa A, Xie G, Taya Y, Araki R, Abe M, Crissman HA, Ouyang H, Li GC, Chen DJ., "DNA-dependent protein kinase-independent activation of p53 in response to DNA damage." J Biol Chem., 274(24):17139-43, June 1999
Woo RA, Jack MT, Xu Y, Burma S, Chen DJ, Lee PW, "DNA damage-induced apoptosis requires the DNA-dependent protein kinase, and is mediated by the latent population of p53." EMBO J., 21(12):3000-8, June 2002
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