Laboratory of Cancer Biology and Genetics, NCI, National Institutes of Health, Bethesda, Maryland 20892; Wistar Institute, Philadelphia, Pennsylvania 19104.
Wistar Institute, Philadelphia, Pennsylvania 19104.
J Biol Chem. 2010 Mar 26;285(13):9636-9641. doi: 10.1074/jbc.M109.062588. Epub 2010 Jan 29.
The tumor suppressor p53 is regulated by numerous post-translational modifications. Lysine methylation has recently emerged as a key post-translational modification that alters the activity of p53. Here, we describe a novel lysine methylation site in p53 that is carried out by two homologous histone methyltransferases, G9a and Glp. G9a and Glp specifically methylate p53 at Lys(373), resulting mainly in dimethylation. During DNA damage, the overall level of p53 modified at Lys(373)me2 does not increase, despite the dramatic increase in total p53, indicating that Lys(373)me2 correlates with inactive p53. Further, reduction of G9a and/or Glp levels leads to a larger population of apoptotic cells. Examination of the Oncomine data base shows that G9a and Glp are overexpressed in various cancers compared with corresponding normal tissues, suggesting that they are putative oncogenes. These data reveal a new methylation site within p53 mediated by the methylases G9a and Glp and indicate that G9a is a potential inhibitory target for cancer treatment.
肿瘤抑制因子 p53 受到多种翻译后修饰的调节。赖氨酸甲基化最近被认为是一种改变 p53 活性的关键翻译后修饰。在这里，我们描述了 p53 中的一个新的赖氨酸甲基化位点，该位点由两个同源的组蛋白甲基转移酶 G9a 和 Glp 执行。G9a 和 Glp 特异性地在赖氨酸 373 位对 p53 进行甲基化，主要导致二甲基化。在 DNA 损伤时，尽管总 p53 急剧增加，但修饰在赖氨酸 373 位的 p53 的总体水平并未增加，表明 Lys(373)me2 与无活性的 p53 相关。此外，降低 G9a 和/或 Glp 的水平会导致更多的凋亡细胞。对 Oncomine 数据库的检查表明，与相应的正常组织相比，G9a 和 Glp 在各种癌症中过度表达，表明它们是潜在的致癌基因。这些数据揭示了由甲基转移酶 G9a 和 Glp 介导的 p53 内的一个新的甲基化位点，并表明 G9a 是癌症治疗的潜在抑制靶点。
