Zhang You-Wei, Hunter Tony, Abraham Robert T
Molecular and Cellular Biology, The Salk Institute, La Jolla, California, USA.
Cell Cycle. 2006 Jan;5(2):125-8. doi: 10.4161/cc.5.2.2308. Epub 2006 Jan 16.
The replication checkpoint monitors the progress of DNA replication forks during S phase, and delays the firing of later replication origins when active replication forks are stalled due to collisions with damaged or abnormally structured DNA. Key components of the replication checkpoint pathway are the apical protein kinase, ATR, and its downstream target kinase, Chk1. Defects in either ATR or Chk1 function result in loss of DNA replication fidelity and cell viability, even in the absence of extrinsic genotoxic stress. Moreover, several clinically important antitumor agents, such as the camptothecins (CPTs), exert their antitumor effects by interfering with DNA replication, and hence the therapeutic response to these drugs is intimately related to signaling through the replication checkpoint. A recent report from this laboratory adds a new facet to the regulatory mechanisms that control the function and duration of checkpoint signaling through the ATR-Chk1 pathway. The results indicate that replication stress induced by a variety of agents, including CPT and deep hypoxia, triggers the ubiquitin-dependent degradation of the checkpoint kinase Chk1 in both normal and transformed human cells. This review provides an overview of the study's major findings, together with their implications for both replication checkpoint function and tumor responsiveness to CPT and related anticancer drugs.
复制检查点在S期监测DNA复制叉的进展，并在活跃的复制叉因与受损或结构异常的DNA碰撞而停滞时，延迟后续复制起点的启动。复制检查点途径的关键成分是顶端蛋白激酶ATR及其下游靶激酶Chk1。即使在没有外源性基因毒性应激的情况下，ATR或Chk1功能的缺陷也会导致DNA复制保真度和细胞活力的丧失。此外，几种临床上重要的抗肿瘤药物，如喜树碱（CPT），通过干扰DNA复制发挥其抗肿瘤作用，因此对这些药物的治疗反应与通过复制检查点的信号传导密切相关。本实验室最近的一份报告为控制通过ATR-Chk1途径的检查点信号传导功能和持续时间的调节机制增添了新的内容。结果表明，由包括CPT和深度缺氧在内的多种因素诱导的复制应激，在正常和转化的人类细胞中都会触发检查点激酶Chk1的泛素依赖性降解。本综述概述了该研究的主要发现，以及它们对复制检查点功能和肿瘤对CPT及相关抗癌药物反应性的影响。
