Mitotic entry upon Topo II catalytic inhibition is controlled by Chk1 and Plk1.,The FEBS Journal

当前位置： X-MOL 学术 › FEBS J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mitotic entry upon Topo II catalytic inhibition is controlled by Chk1 and Plk1.
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-03-06 , DOI: 10.1111/febs.15280
Maria Arroyo ₁ , Ana Cañuelo ₁ , Jesús Calahorra ₁ , Florian D Hastert ₂ , Antonio Sánchez ₁ , Duncan J Clarke ₃ , J Alberto Marchal ₁

Affiliation

Catalytic inhibition of topoisomerase II during G2 phase delays onset of mitosis due to the activation of the so‐called decatenation checkpoint. This checkpoint is less known compared with the extensively studied G2 DNA damage checkpoint and is partially compromised in many tumor cells. We recently identified MCPH1 as a key regulator that confers cells with the capacity to adapt to the decatenation checkpoint. In the present work, we have explored the contributions of checkpoint kinase 1 (Chk1) and polo‐like kinase 1 (Plk1), in order to better understand the molecular basis of decatenation checkpoint. Our results demonstrate that Chk1 function is required to sustain the G2 arrest induced by catalytic inhibition of Topo II. Interestingly, Chk1 loss of function restores adaptation in cells lacking MCPH1. Furthermore, we demonstrate that Plk1 function is required to bypass the decatenation checkpoint arrest in cells following Chk1 inhibition. Taken together, our data suggest that MCPH1 is critical to allow checkpoint adaptation by counteracting Chk1‐mediated inactivation of Plk1. Importantly, we also provide evidence that MCPH1 function is not required to allow recovery from this checkpoint, which lends support to the notion that checkpoint adaptation and recovery are different mechanisms distinguished in part by specific effectors.

中文翻译：

Topo II 催化抑制后的有丝分裂进入由 Chk1 和 Plk1 控制。

由于所谓的串联检查点的激活，G2 期拓扑异构酶 II 的催化抑制会延迟有丝分裂的开始。与广泛研究的 G2 DNA 损伤检查点相比，该检查点鲜为人知，并且在许多肿瘤细胞中受到部分损害。我们最近发现 MCPH1 是一个关键的调节因子，它赋予细胞适应去连接检查点的能力。在目前的工作中，我们探索了检查点激酶 1 (Chk1) 和 polo 样激酶 1 (Plk1) 的贡献，以便更好地了解串联检查点的分子基础。我们的结果表明，Chk1 功能是维持 Topo II 催化抑制诱导的 G2 停滞所必需的。有趣的是，Chk1 功能丧失可以恢复缺乏 MCPH1 的细胞的适应能力。此外，我们证明 Plk1 功能是绕过 Chk1 抑制后细胞中的串联检查点停滞所必需的。综上所述，我们的数据表明 MCPH1 通过抵消 Chk1 介导的 Plk1 失活来实现检查点适应至关重要。重要的是，我们还提供了证据表明 MCPH1 功能不需要允许从该检查点恢复，这支持了这样的观点：检查点适应和恢复是不同的机制，部分由特定效应器区分。

更新日期：2020-03-06

点击分享查看原文

点击收藏

阅读更多本刊最新论文