Chromatin's Role in Repair of Radiation-induced Damage

描述(申请人提供)：辐射诱导的双链断裂(DSB)是对基因组完整性的根本威胁，如果不适当修复，会导致基因组不稳定，进而可能导致癌症和细胞死亡。虽然我们对DSB修复的途径知道很多，但我们对DSB修复是如何在细胞中的自然环境中发生的，即染色质，我们知之甚少。染色质本身就是蛋白质进入DNA的障碍，然而修复机制不知何故能够通过染色质并成功修复DNA损伤。染色质还通过DNA损伤细胞周期检查点在细胞对DNA损伤的反应中发挥关键作用。直到最近，对于如何关闭DNA损伤检查点以使细胞在DNA修复完成后重新进入细胞周期并存活下来，我们的理解存在很大差距。在这个过程中，细胞感觉DNA修复完成的方式是不可或缺的，这也是一个长期存在的谜团。我们最近发现，新修复的DNA上染色质结构的恢复，而不是DNA修复本身，是DNA损伤检查点的失活或“恢复”的难以捉摸的信号(Chen等人，Cell 2008)，以便允许细胞在DSB修复后存活。尽管我们的研究揭示了染色质结构、检查点恢复和DNA修复后细胞周期重新进入之间的新联系，但仍有许多问题有待回答。这项拟议的研究将揭示真核细胞在DNA修复完成后关闭DNA损伤检查点的难以捉摸的机制。通过阐明染色质恢复的机制，携带这种特定的组蛋白修饰信号到DNA损伤检查点机制，即DNA修复完成，我们希望填补我们目前对染色体修复过程的重大空白。我们还将确定与关闭DNA损伤检查点有关的新蛋白质，这些新蛋白质将成为治疗干预的新靶点，以防止癌细胞照射后损伤检查点的失活，以防止癌细胞分裂。

DESCRIPTION (provided by applicant): 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 DNA damage checkpoint is turned off in order to allow cells to reenter the cell cycle and survive after DNA repair is complete. Integral to this process is the way that the cell senses that DNA repair is complete, which has also been a long-standing mystery. We have recently discovered that the restoration of the chromatin structure over the newly-repaired DNA, rather than DNA repair itself, is the elusive signal for inactivation, or "recovery" of the DNA damage checkpoint (Chen et al., Cell 2008) in order to allow cell survival after DSB repair. Although our studies have revealed a novel link between chromatin structure, checkpoint recovery and cell cycle re-entry after DNA repair, many questions remain to be answered. The proposed studies will uncover the elusive mechanism used by eukaryotic cells to turn off the DNA damage checkpoint after DNA repair is complete. By elucidating the mechanism whereby restoration of chromatin carrying this specific histone modification signals to the DNA damage checkpoint machinery that DNA repair is complete, we hope to fill significant gaps in our current knowledge of the chromosomal repair process. We will also identify novel proteins involved in turning off the DNA damage checkpoint that will be novel targets for therapeutic intervention in order to prevent inactivation of the damage checkpoint after irradiation of cancer cells, in order to prevent cancer cells from dividing.