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Chromatin regulation of DNA damage repair (DDR) pathway in radiation resistant Glioblastoma

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Resistance to radiation is a major challenge in the treatment of Glioblastoma. A subset of tumor cells is capable of modulating their DNA damage repair pathway to escape apoptosis, mechanisms of which are still unknown. Since the physiological substrate of DNA damage repair machinery is packed into chromatin, the efficiency of DNA damage repair in a cell must depend on how well the repair factors can gain access to the damaged DNA. Histone modification and chromatin re-modelling are the most important determinants of DNA accessibility. Hence, we are trying to identify differential histone modifications and accompanying changes in chromatin structure of resistant tumor cells that can act as ‘histone marks’ for recruitment of DNA damage repair factors and differential DNA damage response. We are also trying to understand the hierarchical signaling networks that orchestrate chromatin structural changes and coordinate cell-cycle checkpoints to repair broken DNA ends. Understanding of these processes can help us in designing strategies to increase the efficacy of DNA damage based therapeutics in Glioblastoma.

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