Chromatin's Role in Repair of Radiation-induced Damage

描述（由申请人提供）：辐射诱导的双链断裂（DSB）是对基因组完整性的根本威胁，如果不正确修复，会导致基因组不稳定，进而导致癌症和细胞死亡。虽然我们对DSB修复的途径了解很多，但我们对DSB修复在细胞中的自然环境（即染色质）中是如何发生的知之甚少。染色质本质上是蛋白质进入DNA的障碍，然而修复机制却能够以某种方式穿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转导细胞对DNA损伤的反应中起关键作用。直到最近，我们对DNA损伤检查点如何关闭以允许细胞在DNA修复完成后重新进入细胞周期并存活的理解存在很大差距。这一过程不可或缺的是细胞感知DNA修复已完成的方式，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损伤检查点失活或“恢复”的难以捉摸的信号（Chen et al.，Cell 2008），以便在DSB修复后允许细胞存活。虽然我们的研究已经揭示了DNA修复后染色质结构，检查点恢复和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。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。通过阐明携带这种特定组蛋白修饰的染色质的恢复向DNA损伤检查点机制发出DNA修复完成的信号的机制，我们希望填补我们目前对染色体修复过程的知识中的重大空白。我们还将确定参与关闭DNA损伤检查点的新蛋白质，这些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失活，从而防止癌细胞分裂。

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.