Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy.
Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; Division for Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany.
Cell Rep. 2022 Nov 1;41(5):111568. doi: 10.1016/j.celrep.2022.111568.
Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.
基因-环境相互作用可扰乱表观基因组，引发参与癌症发病机制的网络改变。我们将表观基因组学、转录组学和代谢分析与功能干扰相结合，表明肿瘤抑制因子 p53 通过赋予通用甲基供体 S-腺苷甲硫氨酸 (SAM) 的足够水平来维持基因组完整性。在 p53 缺陷细胞中，DNA 甲基化的扰动促进异染色质的去抑制，大量组蛋白 H3-赖氨酸 9 甲基化的丢失，以及随后卫星 RNA 的上调，这引发 R 环相关的复制应激和染色体异常。在 p53 缺陷细胞中，SAM 水平不足是无法对扰动做出反应的基础，因为外源性 SAM 的重新引入会抑制卫星元件并恢复应对应激的能力。从机制上讲，p53 转录控制涉及一碳代谢的基因，包括 Slc43a2，即甲硫氨酸摄取转运蛋白，它对 SAM 合成至关重要。临床数据支持我们的发现，揭示了 p53 介导的代谢在预防非计划 R 环相关基因组不稳定性中的作用。
