期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 3, 页码 718-721出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b07627
关键词
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资金
- Medical Research Council [MRC_MC_U105181009, MRC_MC_UP_A024_1008]
- ERC [200583]
- EMBO ALTF [1232-2011]
- Herchel Smith Fund
- MRC Career Development Fellowship
- Cancer Research U.K. [C14303/A17197]
- MRC [MC_U105181009, MC_UP_A024_1008] Funding Source: UKRI
- European Research Council (ERC) [200583] Funding Source: European Research Council (ERC)
- Cancer Research UK [6934] Funding Source: researchfish
- Medical Research Council [MC_U105181009, MC_UP_A024_1008] Funding Source: researchfish
- Wellcome Trust [099232/Z/12/Z] Funding Source: researchfish
Isocitrate dehydrogenase is mutated at a key active site arginine residue (Arg172 in IDH2) in many cancers, leading to the synthesis of the oncometabolite (R)-2-hydroxyglutarate (2HG). To investigate the early events following acquisition of this mutation in mammalian cells we created a photoactivatable version of IDH2(R172K), in which K172 is replaced with a photocaged lysine (PCK), via genetic code expansion. Illumination of cells expressing this mutant protein led to a rapid increase in the levels of 2HG, with 2HG levels reaching those measured in patient tumor samples, within 8 h. 2HG accumulation is closely followed by a global decrease in 5-hydroxymethylcytosine (5-hmC) in DNA, demonstrating that perturbations in epigenetic DNA base modifications are an early consequence of mutant IDH2 in cells. Our results provide a paradigm for rapidly and synchronously uncloaking diverse oncogenic mutations in live cells to reveal the sequence of events through which they may ultimately cause transformation.
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