DNA Double Strand Break Chromatin Alterations and Genome Integrity

尽管对正常和病理环境下的DNA损伤反应进行了广泛的研究，但 对DNA双链如何发生染色质重组知之甚少 断裂(DSB)并有助于基因组维持和癌细胞健康。现在有了 强有力的证据表明，DSB反应促进了高阶染色质结构的变化。 这部分是由于依赖于DSB的转录改变和DSB诱导的 不同染色体上同源基因组区域之间的重组。这项建议 利用几种新的方法来解决与DSB之间的相互作用相关的问题 染色质改变和基因组完整性。也就是说，(I)DSB依赖染色质是如何 突变导致顺式到双链断裂的转录基因沉默，以及(Ii)双链断裂是如何 诱导的染色体间端粒关联对基因组完整性和生存有贡献吗？ 总体而言，这些研究将解决基因组完整性和 与DSB响应和更高阶之间的通信相关的辐射生物学 染色质结构。

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.