Maddocks Oliver D K, Labuschagne Christiaan F, Adams Peter D, Vousden Karen H
Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, UK.
Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, UK; University of Glasgow Institute of Cancer Sciences, Switchback Road, Glasgow, G61 1QH, UK.
Mol Cell. 2016 Jan 21;61(2):210-21. doi: 10.1016/j.molcel.2015.12.014. Epub 2016 Jan 7.
Crosstalk between cellular metabolism and the epigenome regulates epigenetic and metabolic homeostasis and normal cell behavior. Changes in cancer cell metabolism can directly impact epigenetic regulation and promote transformation. Here we analyzed the contribution of methionine and serine metabolism to methylation of DNA and RNA. Serine can contribute to this pathway by providing one-carbon units to regenerate methionine from homocysteine. While we observed this contribution under methionine-depleted conditions, unexpectedly, we found that serine supported the methionine cycle in the presence and absence of methionine through de novo ATP synthesis. Serine starvation increased the methionine/S-adenosyl methionine ratio, decreasing the transfer of methyl groups to DNA and RNA. While serine starvation dramatically decreased ATP levels, this was accompanied by lower AMP and did not activate AMPK. This work highlights the difference between ATP turnover and new ATP synthesis and defines a vital function of nucleotide synthesis beyond making nucleic acids.
细胞代谢与表观基因组之间的相互作用调节着表观遗传和代谢稳态以及正常细胞行为。癌细胞代谢的变化可直接影响表观遗传调控并促进细胞转化。在此，我们分析了甲硫氨酸和丝氨酸代谢对DNA和RNA甲基化的作用。丝氨酸可通过提供一碳单位从同型半胱氨酸再生甲硫氨酸，从而对该途径产生贡献。虽然我们在甲硫氨酸缺乏的条件下观察到了这种贡献，但出乎意料的是，我们发现丝氨酸在有或没有甲硫氨酸的情况下都通过从头合成ATP来支持甲硫氨酸循环。丝氨酸饥饿会增加甲硫氨酸/ S-腺苷甲硫氨酸的比例，减少甲基向DNA和RNA的转移。虽然丝氨酸饥饿会显著降低ATP水平，但同时AMP水平也较低，且未激活AMPK。这项工作突出了ATP周转与新ATP合成之间的差异，并定义了核苷酸合成在制造核酸之外的重要功能。
