Chromatin's Role in Repair of Radiation-induced Damage

总结 辐射诱导的双链断裂（DSB）是对基因组完整性的根本威胁， 基因组的不稳定性，如果没有得到适当的修复，这反过来又会导致癌症和细胞死亡。虽然我们 虽然我们对DSB修复的途径了解很多，但我们对DSB修复在其组织中是如何发生的知之甚少。 细胞中的自然环境，即染色质。染色质本质上是蛋白质 然而，修复机制却能够以某种方式在染色质中导航， 成功修复DNA损伤染色质在细胞对DNA的反应中也起着关键作用 通过DNA损伤细胞周期检查点的损伤。直到最近，在我们的国家中， 了解DSB修复和DNA损伤检查点如何受到染色质的影响 哺乳动物细胞中的环境。DNA修复机制的进展是这一过程不可或缺的一部分 沿着一个被包装成染色质的基因组;这是如何发生的，以及对表观基因组的影响， 一直是个谜我们最近发现染色质完全分解， 在人类细胞中双链DNA断裂的非同源末端连接期间重新组装。令人兴奋的是， 我们最近的初步数据有力地支持了动态染色质组装到单个核细胞上的积极作用。 单链DNA（ssDNA）在DSB的同源重组修复中间作为内在步骤 DSB修复所需的。组蛋白占据ssDNA以前从未在体内报道过，更不用说 他们扮演着重要的生物学角色。这项研究将揭示组蛋白-DNA的本质 复合物的ssDNA，并将揭示难以捉摸的机制，染色质组装促进DSB 修复人体细胞。通过阐明ssDNA-组蛋白复合物促进DSB的机制， 修复，我们希望填补我们目前对染色体修复过程的知识空白。

SUMMARY Radiation-induced double-strand breaks (DSBs) are fundamental threats to genomic integrity that result in genomic instability if not properly repaired, which can in turn lead to cancer and cell death. Although we know a great deal about the pathways of DSB repair, we know very little about how DSB repair occurs in its natural context in the cell, that is, chromatin. Chromatin by its very nature is an impediment for proteins accessing the DNA, yet the repair machinery is somehow able to navigate through the chromatin and successfully repair DNA damage. Chromatin also plays a key role in transducing the cell's response to DNA damage via the DNA damage cell cycle checkpoint. Until recently, there has been a large gap in our understanding as to how the DSB repair and the DNA damage checkpoint are influenced by the chromatin environment in mammalian cells. Integral to this process is the progression of the DNA repair machinery along a genome that is packaged into chromatin; how this occurs and the influence on the epigenome, has been a long-standing mystery. We have recently shown that chromatin is completely disassembled and reassembled during non-homologous end joining of double-strand DNA breaks in human cells. Excitingly, our recent preliminary data strongly supports an active role for dynamic chromatin assembly onto single stranded DNA (ssDNA) in the midst of homologous recombinational repair of DSBs as an intrinsic step required for DSB repair. Histones occupying ssDNA has never been reported previously in vivo, let alone their playing an important biological role. The proposed studies will uncover the nature of the histone-DNA complexes on ssDNA, and will reveal the elusive mechanism whereby chromatin assembly promotes DSB repair in human cells. By elucidating the mechanism whereby ssDNA-histone complexes contribute to DSB repair, we hope to fill significant gaps in our current knowledge of the chromosomal repair process.