Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC ) and the DNA damage response (DDR ) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC induces p21‐mediated G1 arrest, whereas the DDR requires that cells enter S phase. Gradual inhibition of inosine monophosphate dehydrogenase (IMPDH ), an enzyme required for de novo GMP synthesis, reveals a hierarchical organization of these two checkpoints. We find that the IRBC is the primary nucleotide sensor, but increased IMPDH inhibition leads to p21 degradation, compromising IRBC ‐mediated G1 arrest and allowing S phase entry and DDR activation. Disruption of the IRBC alone is sufficient to elicit the DDR , which is strongly enhanced by IMPDH inhibition, suggesting that the IRBC acts as a barrier against genomic instability.

中文翻译：

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核苷酸耗竭揭示了核糖体生物发生检查点受损，可作为抵抗DNA损伤的屏障。

许多致癌基因可提高核苷酸使用率，从而增加核糖体含量，DNA复制和细胞增殖，但同时触发p53激活。核糖体生物发生检查点受损（IRBC）和DNA损伤反应（DDR）均与核苷酸耗尽后的p53活化有关。但是，很难调和两个检查点一起使用，因为IRBC诱导p21介导的G1阻滞，而DDR则要求细胞进入S期。逐渐抑制肌苷单磷酸脱氢酶（IMPDH），这是从头开始需要的一种酶GMP综合揭示了这两个检查点的层次结构。我们发现IRBC是主要的核苷酸传感器，但增加的IMPDH抑制导致p21降解，损害IRBC介导的G1阻滞并允许S期进入和DDR激活。单独中断IRBC足以引发DDR，而DDR受IMPDH抑制而大大增强，这表明IRBC充当了抗基因组不稳定的屏障。