Laboratory of Cancer Metabolism, ONCOBELL Program, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Spain.
Metabolomics Platform, IISPV & University Rovira i Virgili, Tarragona, Spain.
EMBO J. 2020 Jul 1;39(13):e103838. doi: 10.15252/embj.2019103838. Epub 2020 Jun 2.
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.
许多癌基因增强核苷酸的使用以增加核糖体含量、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（IRBC）和 DNA 损伤反应（DDR）都被认为在核苷酸耗竭后 p53 的激活中起作用。然而，很难协调这两个检查点一起运作，因为 IRBC 诱导 p21 介导的 G1 期阻滞，而 DDR 需要细胞进入 S 期。逐渐抑制肌苷单磷酸脱氢酶（IMPDH），一种用于从头合成 GMP 的酶，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 IMPDH 抑制会导致 p21 降解，从而破坏 IRBC 介导的 G1 期阻滞，并允许 S 期进入和 DDR 激活。单独破坏 IRBC 就足以引发 DDR，而 IMPDH 抑制则强烈增强了 DDR，这表明 IRBC 是防止基因组不稳定性的屏障。
