Mechanistic Link Between DNA Damage Response (DDR) Signaling & Immune Activation




Bhattacharya, Souparno

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Proper maintenance of an intact genome is crucial for cellular homeostasis. To combat threats posed by DNA damage, cells have evolved sophisticated mechanisms - collectively termed as the DNA-damage response (DDR) signaling -, which detect DNA lesions, signal their presence, and promote their repair. Contribution of proper DDR signaling in not just confined to prevention of genomic instability and carcinogenesis, as emerging evidence indicates crosstalk exists at different levels between DDR signaling machinery and our immune system. In my dissertation work, using innovative models and techniques, I deciphered how RAD51, a protein normally associated with repair and replication of DNA, regulates innate immune response. Besides detection and repair of damaged DNA, proper DDR signaling also enables checkpoint activation, which prevents cell cycle progression with unrepaired DNA lesions. In my thesis work, I have proved how failure to arrest cells in the G2-M boundary after genotoxic stress, leads to generation of micronuclei, present in the cytoplasm and subsequent immune activation. Work emanating from my thesis projects will add to the growing body of literature showing how different DDR factors' roles in modulating immune signaling are most often a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Finally, our improving understanding of DDR has already provided new avenues for disease management (e.g. Use of PARP inhibitors in treating BRCA mutant tumors). A more precise understanding of mechanisms by which DDR factors are involved in regulation of cellular immunity can also be exploited to redirect the immune system for both preventing and treating variety of human pathologies including cancer, autoimmune diseases and age related disorders.

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