Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells.
Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells.
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DOI：
10.1016/j.molcel.2015.12.014
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发表时间：
2016-01-21
期刊：
影响因子：
16
通讯作者：
Vousden KH
中科院分区：
文献类型：
--
作者：
Maddocks OD;Labuschagne CF;Adams PD;Vousden KH
细胞代谢和表观基因组之间的串扰调节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以直接影响表观遗传调控并促进转化。在这里，我们分析了蛋氨酸和丝氨酸代谢对DNA和RNA甲基化的贡献。丝氨酸可以通过提供一个碳单元来从同型半胱氨酸再生甲硫氨酸，从而有助于该途径。虽然我们在甲硫氨酸耗尽的条件下观察到这种贡献，但出乎意料的是，我们发现丝氨酸通过从头ATP合成在甲硫氨酸存在和不存在下支持甲硫氨酸循环。丝氨酸饥饿增加蛋氨酸/S-腺苷蛋氨酸的比例，减少甲基转移到DNA和RNA。虽然丝氨酸饥饿显着降低ATP水平，这是伴随着较低的AMP和不激活AMPK。这项工作突出了ATP周转和新ATP合成之间的差异，并定义了核苷酸合成的重要功能，而不仅仅是制造核酸。丝氨酸通过从头ATP合成支持甲硫氨酸循环从头ATP合成是癌细胞中ATP的重要来源甲硫氨酸喂养的结直肠癌细胞不能检测到同型半胱氨酸的再甲基化描述了一种将甲基单元从氨基酸追踪到DNA和RNA上的方法甲硫氨酸循环产生S-腺苷甲硫氨酸（SAM），主要的细胞甲基供体。丝氨酸可以提供一个碳单元以从高半胱氨酸再生甲硫氨酸。Maddocks等人表明在结肠直肠癌细胞中，丝氨酸也通过从头ATP合成维持甲硫氨酸循环，这支持甲硫氨酸转化为SAM。
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. Serine supports the methionine cycle through de novo ATP synthesis De novo ATP-synthesis is an important source of ATP in cancer cells Methionine fed colorectal cancer cells do not detectably re-methylate homocysteine A method to track methyl units from amino acids onto DNA and RNA is described The methionine cycle generates S-adenosyl methionine (SAM), the primary cellular methyl donor. Serine may provide one-carbon units to regenerate methionine from homocysteine. Maddocks et al. show that in colorectal cancer cells serine also maintains the methionine cycle through de novo ATP synthesis, which supports the conversion of methionine to SAM.