Present Position and Address

6.136 Medical Research Building
Route: 1079
Telephone: (409) 772-1780
Fax: (409) 747-8608
E-mail: samitra@utmb.edu

B.S. 1957 Calcutta University, Calcutta, India
M.S. 1959 Calcutta University, Calcutta, India
Ph.D. 1964 University of Wisconsin, Madison

RESEARCH INTERESTS:

The research theme in the Mitra Laboratory is repair of oxidative DNA damage in mammals, its regulation, and its impact on apoptosis and drug resistance of tumor cells. Reactive oxygen species (ROS), which react with most cellular macromolecules, are continuously generated during respiration, and are also induced exogenously due to inflammation, infection and anti-tumor drug treatment. Even though a variety of cellular processes have evolved to inactivate ROS, oxidative stress is required for many cellular signaling processes to maintain homeostasis. ROS are also genotoxic, and generate a wide variety of lesions in both nuclear and mitochondrial genomes, which are repaired primarily via the base excision repair (BER) pathway.

8-oxoguanine-DNA glycosylase (OGG), and AP-endonuclease (APE), two key enzymes in repair of oxidative DNA damage, are the major topics of investigation in the Mitra Laboratory. The studies cover a wide range of aspects including structure/function studies of these enzymes, identification and cloning of mitochondria-specific APE, posttranslational modifications of APE and OGG and their in vivo significance, and the signaling mechanism of nuclear accumulation of these proteins in response to oxidative stress. The major mammalian APE, APE1, is essential for embryonic mouse development. A conditional knockout mutant line has been generated to elucidate the essential function of the enzyme. APE1 has two additional repair-unrelated functions in the regulation of many genes, including its own. Significant efforts are being made to unravel the mechanism of regulation and to identity its partners therein.

The Mitra Lab recently discovered two new human DNA glycosylases specific for oxidized bases. These enzymes have unusual properties which suggest their involvement in replication and/or transcription coupled repair. The reaction mechanism of these enzymes also led to the development of a new paradigm of base excision repair which does not require APE but uses polynucleotide kinase instead.
Aging is a complex phenotype resulting from decline in many cellular functions and replicative senescence; chronic oxidative stress has been implicated in its etiology. The effects of aging on the multitude of activities of APE1 are being studied in a project supported by the National Institute on Aging.
Finally, one mechanism for development of resistance to alkylating antitumor drugs in tumor cells appears to be the prevention of tumor cell apoptosis. These drugs induce ROS and mitochondrial dysfunction, in which p53 plays a critical role. One project (in collaboration with I. Boldogh, Microbiology & Immunology, UTMB) aims at identification of potential targets for adjuvant therapy to reverse drug resistance.
Major source of financial support includes grants from the National Cancer Institute, National Institute for Environmental Health Sciences, in addition to National Institute on Aging (as part of a Program Project). Additional support comes from a second Program Project, entitled, "Structural Cellular Biology of DNA Repair Machines", which involves 12 institutions in the U.S.

1. Dou, H., Mitra, S. and Tapas K. Hazra, T. K. Repair of Oxidized Bases in DNA Bubble Structures by Human DNA Glycosylases NEIL1 and NEIL2. J. Biol. Chem. 278:49679-49684, 2003.
2. Bhakat, K. K., Izumi, T., Yang, S. H., Hazra, T. K. and Mitra, S. Role of Acetylated Human AP-endonuclease (APE1/Ref-1) in Regulation of the Parathyroid Hormone Gene, EMBO J. 22:6299-6309, 2003.
3. Szczesny, B., Hazra, T. K., Papaconstantinou, J., Mitra, S. and Boldogh, I. Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. PNAS 100:10670-10675, 2003. *(Special press release by PNAS.)
4. Hazra, T. K., Kow, Y. W., Hatahet, Z., Imhoff, B., Boldogh, I., Mokkapati, S. K., Mitra, S., and Izumi, T. Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions. J. Biol. Chem., 277:30417-30420, 2002.
5. Hazra, T. K.; Izumi, T.; Boldogh, I.; Imhoff, B.; Kow, Y. W.; Jaruga, P.; Dizdaroglu, M. Identification and characterization of a human DNA glycosylase for repair in modified bases in oxidatively damaged DNA. PNAS, 99:3523-3528, 2002.
6. Mol. C.D., Izumi, T., Mitra, S. and Tainer, J.A. DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination. Nature 403:451–456, 2000.
7. Bhakat, K. B., Hazra, T. K. and Mitra, S. Acetylation of the Human DNA Glycosylase NEIL2 and Inhibition of Its Activity. Nucleic Acids Res. 32, 3033-3039, 2004.
8. Wiederhold, L., Leppard, J. B., Kedar, P., Karimi-Busheri, F., Rasouli-Nia, A., Weinfeld, M., Tomkinson, A. E., Izumi, T., Prasad, R., Wilson, S. H., Mitra, S., and Hazra, T. K. AP Endonuclease-independent DNA Base Excision Repair in Human Cells. Molecular Cell, In Press, 2004.
9. Mokkapati, S. K., Wiederhold, L., Hazra, T. K., and Mitra, S. Stimulation of DNA Glycosylase Activity of OGG1 by NEIL1: Functional Collaboration Between Two Human DNA Glycosylases. Biochemistry, In Press, 2004.