Nucleotide imbalance decouples cell growth from cell proliferation.
Nucleotide imbalance decouples cell growth from cell proliferation.
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DOI：
10.1038/s41556-022-00965-1
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发表时间：
2022-08
影响因子：
21.3
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中科院分区：
文献类型：
--
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核苷酸代谢支持RNA合成和DNA复制，使细胞生长和分裂。核苷酸耗尽可以抑制细胞生长和增殖，但细胞如何感知和响应单个核苷酸相对水平的变化尚不清楚。此外，生物质生产的核苷酸需求在细胞周期过程中发生变化，细胞如何协调不同的核苷酸需求与细胞周期进程还没有很好地理解。在这里，我们发现过量的单个核苷酸可以通过破坏DNA复制所需的核苷酸碱基的相对水平并阻碍DNA复制来抑制增殖。由此产生的嘌呤和嘧啶失衡不会被典型的生长调节途径（例如mTORC 1、Akt和AMPK信号级联）感知到，尽管增殖受到抑制，但仍导致细胞过度生长。相反，细胞依赖于复制应激信号传导在S期期间的核苷酸不平衡期间存活并从其恢复。我们发现ATR依赖的复制应激信号在未受干扰的S期被激活，并促进核苷酸的可用性，以支持DNA复制。总之，这些数据表明，直到S期才检测到不平衡的核苷酸水平，使细胞依赖于复制应激信号来科普这种代谢问题，并破坏细胞生长和分裂的协调。Diehl等人表明，核苷酸种类之间的不平衡不被典型的代谢调节途径所感知，尽管DNA复制阻断，但仍导致细胞过度生长。正常S期需要ATR来增加核苷酸的利用率。
Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication and impeding DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways like mTORC1, Akt and AMPK signalling cascades, causing excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signalling to survive during, and recover from, nucleotide imbalance during S phase. We find that ATR-dependent replication stress signalling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signalling to cope with this metabolic problem and disrupting the coordination of cell growth and division. Diehl et al. show that imbalance among nucleotide species is not sensed by canonical metabolic regulatory pathways, causing excessive cell growth despite a DNA replication block. ATR is needed to increase nucleotide availability in normal S phase.
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