Replication Catastrophe: When a Checkpoint Fails because of Exhaustion
Replication Catastrophe: When a Checkpoint Fails because of Exhaustion
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DOI：
10.1016/j.molcel.2017.05.001
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发表时间：
2017-06-15
期刊：
影响因子：
16
通讯作者：
Lukas, Jiri
中科院分区：
文献类型：
--
作者：
Toledo, Luis;Neelsen, Kai John;Lukas, Jiri
增殖细胞依赖于所谓的DNA复制检查点来确保基因组复制的有序完成，其故障可能导致灾难性的基因组破坏，包括复制起点的非计划性发射，复制叉的停滞和崩溃，大规模DNA断裂，以及最终的细胞死亡。尽管对真核生物复制检查点的分子基础进行了多年的深入研究，但其失败的悲惨后果的机制仍然是个谜。最近的发展提供了一个统一的模型，其中的复制检查点防止全局耗尽的速率限制复制调节器。在这里，我们讨论了这种机制如何防止灾难性的基因组破坏，并建议如何利用这些知识来推进治疗策略，以消除在DNA复制压力增加的情况下固有增殖的癌细胞。
Proliferating cells rely on the so-called DNA replication checkpoint to ensure orderly completion of genome duplication, and its malfunction may lead to catastrophic genome disruption, including unscheduled firing of replication origins, stalling and collapse of replication forks, massive DNA breakage, and, ultimately, cell death. Despite many years of intensive research into the molecular underpinnings of the eukaryotic replication checkpoint, the mechanisms underlying the dismal consequences of its failure remain enigmatic. A recent development offers a unifying model in which the replication checkpoint guards against global exhaustion of rate-limiting replication regulators. Here we discuss how such a mechanism can prevent catastrophic genome disruption and suggest how to harness this knowledge to advance therapeutic strategies to eliminate cancer cells that inherently proliferate under increased DNA replication stress.