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Checkpoint Adaptation Precedes Spontaneous and Damage-Induced Genomic Instability in Yeast

机译：检查点适应优先于酵母中自发和损伤诱导的基因组不稳定

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Despite the fact that eukaryotic cells enlist checkpoints to block cell cycle progression when their DNA is damaged, cells still undergo frequent genetic rearrangements, both spontaneously and in response to genotoxic agents. We and others have previously characterized a phenomenon (adaptation) in which yeast cells that are arrested at a DNA damage checkpoint eventually override this arrest and reenter the cell cycle, despite the fact that they have not repaired the DNA damage that elicited the arrest. Here, we use mutants that are defective in checkpoint adaptation to show that adaptation is important for achieving the highest possible viability after exposure to DNA-damaging agents, but it also acts as an entrée into some forms of genomic instability. Specifically, the spontaneous and X-ray-induced frequencies of chromosome loss, translocations, and a repair process called break-induced replication occur at significantly reduced rates in adaptation-defective mutants. This indicates that these events occur after a cell has first arrested at the checkpoint and then adapted to that arrest. Because malignant progression frequently involves loss of genes that function in DNA repair, adaptation may promote tumorigenesis by allowing genomic instability to occur in the absence of repair.
机译：尽管真核细胞在DNA受损时仍需要检查点来阻止细胞周期的进程，但细胞仍会自发发生或对遗传毒性剂产生频繁的基因重排。我们和其他人以前已经描述了一种现象（适应性），其中被DNA损伤检查点捕获的酵母细胞最终会超过该捕获并重新进入细胞周期，尽管事实上它们没有修复引起捕获的DNA损伤。在这里，我们使用在检查点适应性方面存在缺陷的突变体来表明适应性对于在暴露于DNA破坏剂后实现最大的生存力很重要，但是它也可以作为某些形式的基因组不稳定性的输入。具体而言，在适应缺陷型突变体中，染色体丢失，易位和称为断裂诱导复制的修复过程的自发频率和X射线诱导频率以明显降低的速率发生。这表明这些事件是在细胞首先停在检查站然后适应该停滞之后发生的。由于恶性进展经常涉及在DNA修复中起作用的基因的丧失，因此适应性疾病可以通过在不进行修复的情况下发生基因组不稳定来促进肿瘤发生。

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