Radiation remains an important treatment modality in the therapy of breast cancer. Ionizing radiation induces DNA double strand breaks, which initiates a characteristic response. ATM and related protein kinases recognize each break and phosphorylate adjacent histone H2AX, promoting assembly of ionizing radiation induced foci (IRIF), multiprotein signaling and repair complexes spread over megabases of the surrounding chromatin. The resulting amplification mediates its effects by activating downstream kinases to induce cell cycle arrest, DNA repair, and apoptotic responses. This project is directed toward developing a novel reporter of DNA damage response that will allow tracking of the formation and resolution of DNA damage foci in normal and breast cancer cells. Toward these ends, we will develop fluorescent protein fusions based on 53BP1 that accumulate at double strand breaks, and use these fusion proteins as probes to identify proteins that constitute IRIF. This new technology can be used to determine the radiation responses of tumors and normal tissues and to discover new biological targets to enhance radiation effects.
Radiation therapy is an important tool in breast cancer therapy, but it is rarely curative. This work will develop a tool to help predict the effects of radiation therapy and to discover new agents that may improve outcomes for patients receiving radiotherapy.
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