Despite extensive study of DNA damage responses in both normal and pathologic settings, it is poorly understood how chromatin reorganization occurs in response to DNA double-strand breaks (DSBs) and contributes to genome maintenance and cancer cell fitness. There is now strong evidence that DSB responses promote changes in higher order chromatin structure. These arise in part by DSB dependent alterations in transcription, and by DSB induced recombination between homologous genomic regions on different chromosomes. This proposal utilizes several novel approaches to address questions related to the interplay between DSB chromatin alterations and genome integrity. Namely, (i) How do DSB dependent chromatin alterations contribute to transcriptional gene silencing in cis to DSBs, and (ii) how do DSB induced inter-chromosomal telomere associations contribute to genome integrity and survival? Collectively, these investigations will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB responses and higher order chromatin structure.
Despite extensive study of DNA damage responses in both normal and pathologic settings, it is poorly understood how chromatin reorganization occurs in response to DNA double-strand breaks (DSBs) and contributes to genome maintenance and cancer cell fitness. My group has shown that DSB responses promote ATM dependent alterations in transcription, and recombination dependent changes in higher order chromatin associations. We propose to use novel experimental systems to address how higher order chromatin changes are enacted by DNA damage responses, and how they impact genome integrity and survival to DSBs.
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