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1. Models to assess the effects of IUdR incorporation on the cell cycle
2. A systems biology approach towards understanding the mechansim of Base Excision Repair (BER) in the processing of IUdR
The DNA repair mechanisms have been utilized in their binary status for achieving therapeutic gain in cancer patients. A proficient mismatch repair (MMR) system helps mediate the cytotoxicity of several chemotherapeutic drugs whereas the deficient tumors have been exploited with their increased susceptibility to radiosensitizer mediated ionizing radiation treatment. The molecular mechanisms lying at the core of these activities are in the form of a web with connecting links cutting across different modes of DNA repair. We propose to take an integrative approach to understand the interplay of the DNA repair mechanisms related to the processing of a potent radiosensitizer, 5-Iododeoxyuridine (IUdR). Base excision repair (BER) is the major DNA repair pathway involved in ionizing radiation induced DNA damage and the removal of incorrect or damaged bases. A complete understanding of the function of base excision repair as operative on IUdR generated mispairs will give important leads into the application of this radiosensitizer in radiotherapy. Kinetic measurement of the steps of this important repair mechanism is needed to assign its share in the processing of IUdR and abrogate the function of crucial proteins to achieve a therapeutic gain. An important enzyme involved in BER has been attractive in displaying functions which could lead to the integration of two major DNA repair pathways – MMR and BER. Our studies would revolve around this molecule – MED1 and try to integrate the diverse functions assigned to this molecule by independent studies. To lend a more realistic perspective to these efforts, we finally propose to develop versatile and sensitive in vivo assays to monitor DNA repair activity within the cells in their natural environment
3. Understanding death pathways ! An attempt to integrate Apoptosis, Senescence and Autophagy
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