The ability of cells to detect and repair DNA double-strand breaks (DSBs) created by ionizing radiation can be limited by the chromatin structure surrounding the lesion. Cells therefore need to remodel the local chromatin structure at the DSB to gain access to the site and to process and repair the DSB. However, the chromatin remodeling complexes which drive changes in chromatin organization at DSBs are poorly defined. The NuA4-Tip60 remodeling complex is rapidly recruited to DSBs, where it functions to reorganize the local chromatin structure, creating open, flexible domains which are essential for the detection and repair of DSBs. NuA4-Tip60 functions to both exchange novel histone variants onto nucleosomes at the DSB and to promote hyperacetylation of histones, both of which favor the formation of open chromatin. Importantly, NuA4-directed remodeling of the chromatin at DSBs is required for controlling histone modification, loading of DSB repair proteins, controlling end resection of the break and choice of repair pathway. The central hypothesis is that NuA4-Tip60 creates open, flexible chromatin at DSBs and regulates end processing of the damaged DNA. Our approach is to utilize Zinc Finger Nucleases to create targeted DSBs in both compact intergenic regions and in transcribed genes to explore the differences in DSB repair between these distinct domains. We will determine how NuA4 promotes the spreading of histone acetylation and exchange of histone H2A.Z, and determine how these 2 processes weaken interaction between adjacent nucleosomes and promote the formation of open, flexible chromatin. We will determine how NuA4-Tip60 positions nucleosomes either side of the DSB and how this positioning regulates end resection, processing of the DSB and choice of DSB repair pathway. Further, we will determine how recruitment of the chromatin structural protein Brd2 to DSBs imposes specific functional order on the chromatin and regulates cellular radiosensitivity. In addition, we will determine how JQ1, a novel bromodomain inhibitor which blocks Brd2 recruitment to DSBs, inhibits chromatin reorganization at DSBs and sensitizes cells to ionizing radiation. This project will provide insigh into how DSBs created by ionizing radiation leads to specific structural re-organization of the chromatin by NuA4-Tip60. Further, it will determine how nucleosome reorganization impacts the mechanism and fidelity of DSB repair in both genes and silent, intergenic regions. In addition, we will determine if JQ1 provides the basis for a new class of anti-cancer agents which function to block chromatin reorganization at DSBs and sensitize tumors to radiation therapy. Finally, the chromatin landscape in tumor cells is frequently altered, including unique patterns of histone modifications, altered chromatin packing and altered expression/mutation of chromatin regulatory proteins, including components of the NuA4-Tip60 complex. This work will provide new insight into how NuA4-directed chromatin reorganization impacts DSB repair in tumor cells, and define how altered chromatin structure in tumors impacts tumor progression and the sensitivity of tumors to both radiation therapy and chemotherapy.
Chromatin organization and histone modifications are frequently altered in tumors and may contribute to the inherent resistance of these tumors to radiation therapy. By identifying the chromatin factors which regulate chromatin structure during the detection and repair of DNA damage caused by ionizing radiation, we can identify new targets for development of clinical radiation sensitizers. Understanding how mutations or alterations in chromatin regulatory proteins and chromatin structure influences sensitivity to radiation and chemotherapy can be used to guide choice of cancer therapy and predict outcome.
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