DNA replication stress: NoCut to the rescue
DNA replication stress: NoCut to the rescue
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DOI：
10.1080/15384101.2016.1214044
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Mendoza, Manuel
中科院分区：
文献类型：
--
作者：
Amaral, Nuno;Brownlow, Nicola;Mendoza, Manuel
众所周知，检查点系统在细胞中起作用，通过有丝分裂抑制进程，直到在先前阶段检测到的错误已经正确完成。然而，在染色体后期开始后，保护细胞免受染色体分离错误的机制尚不清楚。然而，晚期分离错误，如染色体滞后和后期桥，在正常情况下并不罕见，在肿瘤中也很常见。因此，后期分离的DNA暴露在细胞分裂机制的潜在损害中。细胞对这种威胁有何反应？我们之前提出，在出芽酵母中，一个依赖于aurora - b的监测系统，称为NoCut检查点，通过抑制细胞质分裂的完成来响应晚期DNA分离错误，直到染色质从卵裂面被清除。1-2随后在人细胞中发现了一个与NoCut同源的aurora - b依赖性脱落检查点。然而，目前尚不清楚在什么生理条件下NoCut被激活，同样重要的是，在什么条件下检查点防止DNA桥断裂。在最近的一项研究中，我们确定了出芽酵母细胞如何对各种类型的染色质桥作出反应。利用延时荧光显微镜和电子断层扫描，我们发现极光b依赖的NoCut检查点在响应凝缩蛋白和拓扑异构酶II功能失活引起的染色质桥时延迟脱落。然而，在这两种情况下，DNA断裂最终会发生，这可能与在缺乏凝聚蛋白或拓扑异构酶II的情况下桥不能被解决有关，这是染色体分离所必需的。这就提出了NoCut检查点是否可以在细胞分裂过程中防止DNA损伤的问题。我们发现，在暴露于羟基脲后，存在由DNA复制应激引起的桥，野生型细胞以依赖于Aurora B的方式延迟脱落，在这种情况下，NoCut确实可以防止DNA损伤并确保细胞存活。我们确定了对DNA桥反应的脱落抑制的2个基本要求。首先，Aurora-B激酶必须是活跃的，并且在细胞分裂过程中与纺锤体中间区的微管相关。这些发现表明，极光B
It is well known that checkpoint systems operate in the cell to inhibit progression through mitosis until errors detected in previous stages have been properly completed. Less is known, however, about mechanisms protecting cells against errors in chromosome segregation after anaphase has begun. Yet late segregation errors, such as lagging chromosomes and anaphase bridges, are not rare in normal conditions, and are frequent in tumors. Late-segregating DNA is thus exposed to potential damage by the cell division machinery. How do cells react to such a threat?We previously proposed that in budding yeast, an Aurora-B-dependent monitoring system, termed the NoCut checkpoint, responds to late DNA segregation errors by inhibiting completion of cytokinesis until chromatin is cleared from the cleavage plane. 1-2 An Aurora-B-dependent abscission checkpoint homologous to NoCut was subsequently identified in human cells. 3 However, it remained unclear under what physiological conditions NoCut is activated, and equally importantly, under what conditions the checkpoint prevents DNA bridge breakage. In a recent study, 4 we determined how budding yeast cells respond to various types of chromatin bridges. Using time-lapse fluorescence microscopy and electron tomography, we found that the Aurora-B-dependent NoCut checkpoint delays abscission in response to chromatin bridges caused by inactivation of condensin and Topoisomerase II function. However, DNA breaks eventually occur in these 2 cases, probably linked to the fact that bridges cannot be resolved in the absence of condensin or Topoisomerase II, which are essential for chromosome segregation. This raised the question of whether the NoCut checkpoint can prevent DNA damage during cytokinesis. We found that in the presence of bridges caused by DNA replication stress after exposure to hydroxyurea, wild type cells delay abscission in a manner dependent on Aurora B, and that in this case NoCut does prevent DNA damage and ensures cell survival. We identified 2 essential requirements for abscission inhibition in response to DNA bridges. Firstly, Aurora-B kinase must be active and associated with microtubules of the spindle midzone during cytokinesis. 2 These findings suggest that Aurora B