Cell cycle progression is characterized by the periodic synthesis and destruction of a host of regulatory proteins that produces oscillating waves of activity, such as cyclin‐dependent kinase (Cdk) activity, to drive unidirectional advancement through the cell cycle. These waves of activity also ensure cells select the optimal mechanism to repair damaged DNA. Cells utilize two major DNA repair pathways, non‐homologous end joining (NHEJ) and homologous recombination (HR).^[1^] NHEJ is a rapid and efficient means of repair, but is potentially mutagenic. HR, in contrast, utilizes homologous DNA sequences as a template for faithful repair and is limited to parts of the cell cycle (mid‐late S and G2) when sister chromatids are present in the cell and elevated Cdk activity promotes the use of HR. Sister chromatids are of course present in mitosis as well. However, the faithful segregation of chromosomes in mitosis is critical for genome stability and chromosomes condense to facilitate the movement of such large units of DNA. It is critical that no physical links between sister chromatids, such as HR intermediates, are present at anaphase, which would lead to chromosome mis‐segretion and/or DNA damage. Thus, although damage occurring in mitosis is sensed, mitotic cells actively inhibit DNA repair and also induce mechanisms specifically tasked with resolving any intermediates or other linkages that remain in early mitotic chromosomes.^[1^] Interestingly, while Cdk activity promotes HR in S and G2, the higher levels of Cdk activity in mitosis ultimately blocks both cell cycle checkpoint signaling and DNA repair.^[1^]

In an Ideas and Speculation article in this issue of BioEssays, Machín and Ayra‐Plasencia discuss their recent discovery that challenges long held dogmas of mitotic progression and mitotic responses to DNA damage.^[2^] First, the authors found that DNA damage occurring during telophase in budding yeast elicits a checkpoint‐mediated mitotic delay and is repaired by HR.^[3^] Biochemically, telophase may represent a unique window in mitosis that is permissive for HR‐mediated repair. The triggering of cyclin destruction at anaphase onset leads to loss of Cdk activity and the dephosphorylation of Cdk substrates. It is conceivable that differential rates or timing of substrate dephosphorylation could reverse inhibitory phosphorylation of proteins required for checkpoint activity and HR while maintaining HR‐promoting phosphorylation.^[4^] Or, perhaps a phosphatase is triggered by the DNA damage checkpoint in telophase to promote these conditions. Second, whereas sister chromatids are in close proximity during S and G2, those in telophase are not. To overcome this barrier to using HR, yeast relocalize the mitotic kinesin Cin8, perturbing spindle elongation and allowing the sister chromatids to coalesce to allow repair.^[3^] While this idea is in contrast to the concept of irreversible cell cycle progression, it is known that in very early mitosis a reversion in chromatin condensation can occur to allow DNA repair in human cells.^[5^] Whether a point‐of‐no‐return (e.g., chromosomes become too far apart) exists in this telophase response as it does in early mitosis remains unknown.

These findings prompt new questions regarding our understanding of the mechanisms regulating the cell cycle and genome. Machín and Ayra‐Plasencia address several key questions and discuss potential biological rationale for why such unexpected events may take place in yeast and the potential for similar mechanisms to be utilized in higher eukaryotes, namely humans, as well as the challenges of testing this model in more complex cells.

细胞周期进程的特点是周期性地合成和破坏大量调节蛋白，这些蛋白会产生振荡的活动波，例如细胞周期蛋白依赖性激酶（Cdk）活性，从而推动细胞周期的单向前进。这些活动波也确保细胞选择修复受损DNA的最佳机制。细胞利用两种主要的DNA修复途径：非同源末端连接（NHEJ）和同源重组（HR）。^[ 1 ^]NHEJ是一种快速有效的修复手段，但可能具有致突变性。相比之下，HR利用同源DNA序列作为忠实修复的模板，并且当细胞中存在姐妹染色单体且Cdk活性升高促进HR的使用时，HR仅限于部分细胞周期（中晚期S和G2）。姐妹染色单体当然也存在于有丝分裂中。然而，有丝分裂中染色体的忠实分离对于基因组的稳定性至关重要，并且染色体凝聚以促进这种大单位DNA的移动。至关重要的是后期时姐妹染色单体之间不存在物理联系，例如HR中间体，否则会导致染色体错误分离和/或DNA损伤。因此，尽管感觉到有丝分裂中发生的损害，^[ 1 ^]有趣的是，虽然Cdk活性可促进S和G2的HR，但有丝分裂中Cdk活性的较高水平最终会阻断细胞周期检查点信号传导和DNA修复。^[ 1 ^]

Machín和Ayra-Plasencia在本期BioEssays的《观点与推测》文章中讨论了他们最近的发现，即长期挑战有丝分裂进展和对DNA损伤的有丝分裂反应的教条。^[ 2 ^]首先，作者发现发芽酵母在末期发生的DNA损伤引起检查点介导的有丝分裂延迟，并被HR修复。^[ 3 ^]从生化角度看，末期可能代表有丝分裂的唯一窗口，允许HR介导的修复。后期开始时细胞周期蛋白破坏的触发导致Cdk活性的丧失和Cdk底物的去磷酸化。可以想象，底物去磷酸化的不同速率或时间可以逆转检查点活性和HR所需蛋白的抑制性磷酸化，同时保持HR促进磷酸化。^[ 4 ^]或者，可能是由于末期的DNA损伤检查点触发了磷酸酶，从而促进了这些状况。其次，虽然姐妹染色单体在S和G2期间非常接近，但在末期染色单体却没有。为了克服使用HR的障碍，酵母将有丝分裂驱动蛋白Cin8重新定位，扰动纺锤体伸长并允许姐妹染色单体聚结以进行修复。^[ 3 ^]尽管这种想法与不可逆的细胞周期进程的概念相反，但众所周知，在极早期的有丝分裂中，染色质浓缩会发生逆转，从而可以修复人类细胞中的DNA。^[ 5 ^] 这种末期反应是否像早期有丝分裂一样存在不返回点（例如，染色体变得太远）。

这些发现引发了关于我们对调节细胞周期和基因组机制的理解的新问题。Machín和Ayra-Plasencia回答了几个关键问题，并讨论了潜在的生物学原理，说明了为什么此类意外事件可能在酵母中发生，以及类似机制在人类等高等真核生物中的应用潜力，以及在该模型中测试该模型所面临的挑战更复杂的细胞。