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首页> 外文期刊>Cell cycle >TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation.
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TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation.

机译：TopBP1和​​DNA聚合酶α介导的9-1-1复合物募集到停滞的复制叉中：对基于复制重启的ATR检查点激活机制的影响。

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摘要

Upon sensing DNA damage or replication stress, cells trigger checkpoint response pathways that control cell cycle progression and maintain genomic stability. A variety of DNA lesions can activate the ATR (ATM and Rad3-related) protein kinase, which phosphorylates its critical substrate Chk1 to relay the checkpoint signal. ATR activation requires several factors, including the BRCT repeat-containing TopBP1 protein and the 9-1-1 clamp protein. Here, we summarize recent advances in understanding the multiple roles played by TopBP1 in ATR activation at stalled replication forks. We review recent studies showing that TopBP1 controls the loading of 9-1-1 onto stalled replication forks via a pathway that also requires DNA polymerase alpha (pol alpha). Based on these recent studies, we present a revised model for ATR activation, and speculate that TopBP1-mediated recruitment of pol alpha and 9-1-1 may couple checkpoint activation to replication restart, when DNA synthesis is blocked on the leading strand of a replication fork. Lastly, we present a new experiment that examines how TopBP1 binds to stalled replication forks, and we identify important new questions that our recent studies have raised regarding how stalled replication forks are sensed by the ATR checkpoint pathway.
机译：一旦检测到DNA损伤或复制压力，细胞就会触发检查点响应途径，从而控制细胞周期进程并保持基因组稳定性。多种DNA损伤均可激活ATR（ATM和Rad3相关）蛋白激酶，该蛋白激酶将其关键底物Chk1磷酸化以传递检查点信号。 ATR激活需要几个因素，包括含BRCT重复序列的TopBP1蛋白和9-1-1钳位蛋白。在这里，我们总结了最近的进展，了解了停滞的复制叉中TopBP1在ATR激活中扮演的多个角色。我们回顾了最近的研究，这些研究表明TopBP1通过一条还需要DNA聚合酶α（pol alpha）的途径控制9-1-1装载到停滞的复制叉上。基于这些最新研究，我们提出了ATR激活的修订模型，并推测当DNA合成在Aβ的前导链上受阻时，TopBP1介导的pol alpha和9-1-1的募集可能将检查点激活与复制重启耦合。复制叉。最后，我们提出了一个新的实验，检查TopBP1如何与停滞的复制叉绑定，并且我们确定了我们最近的研究提出的有关ATR检查点途径如何感测停滞的复制叉的重要新问题。

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