Mitotic Catastrophe and the Mitotic Exit DNA Damage Checkpoint

描述（由申请方提供）：DNA损伤对细胞周期进程的影响具有细胞周期阶段依赖性。在有丝分裂中，DNA损伤诱导有丝分裂灾难，其表现为细胞死亡或胞质分裂失败。后者通过p53依赖的四倍体检查点导致双核细胞的形成和细胞周期停滞在G1状态。目前尚不清楚胞质分裂的失败是与受损DNA相关的机械问题的结果，还是一个受调控的过程。最近，我们发现在哺乳动物细胞中存在有丝分裂出口DNA损伤检查点，其阻止胞质分裂。我们认为，这个检查点是负责有丝分裂灾难和功能的最后一道防线，在保持基因组的稳定性。我们将确定检查点用于停止有丝分裂和诱导有丝分裂灾难的机制，并将确定此检查点的生理意义。

DESCRIPTION (provided by applicant): The impact of DNA damage on cell cycle progression is cell cycle stage dependent. In mitosis, DNA damage induces mitotic catastrophe which is manifested as either cell death or failure of cytokinesis. The latter leads to the formation of binucleated cells and cell cycle arrest in Gl state via the p53-dependent tetraploid checkpoint. It is not clear whether the failure of cytokinesis is a result of mechanical problems associated with the damaged DNA or is a regulated process. Recently, we discovered the presence of a mitotic exit DNA damage checkpoint in mammalian cells that prevents cytokinesis. We propose that this checkpoint is responsible for mitotic catastrophe and functions as the last line of defense in preserving genome stability. We will identify mechanisms used by the checkpoint to stop mitosis and to induce mitotic catastrophe, and will determine the physiological significance of this checkpoint.