Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
Oncogene. 2012 May 3;31(18):2335-49. doi: 10.1038/onc.2011.415. Epub 2011 Oct 3.
Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.
病毒蛋白的表达会导致重要的表观遗传改变，从而导致异常的细胞生长。病毒蛋白是否直接靶向组蛋白甲基转移酶（HMTs），即表观遗传调控的关键家族酶，并调节其酶活性，目前仍不清楚。在这里，我们发现低危型和高危型人乳头瘤病毒（HPV）的 E6 蛋白都与三种共激活 HMTs，即 CARM1、PRMT1 和 SET7 相互作用，并在体外和 HPV 转化的 HeLa 细胞中下调它们的酶活性。此外，这三种 HMTs 对于 E6 减弱 p53 反式激活功能是必需的。在机制上，E6 阻碍了 CARM1 和 PRMT1 催化的 p53 反应启动子上的组蛋白甲基化，并独立于 E6 介导的 p53 降解抑制 p53 与染色质化 DNA 的结合。由 SET7 催化的赖氨酸-372 位预甲基化的 p53（p53K372 单甲基化）可保护 p53 免受 E6 诱导的降解。一致地，E6 下调了 p53K372 单甲基化，从而降低了 p53 蛋白稳定性。由于 E6 介导的 HMT 活性抑制，p53 下游基因的表达受到抑制。总之，我们的研究结果不仅揭示了病毒干扰 p53 功能的一种巧妙方法，而且还证明了 HMT 活性的调节是病毒癌蛋白进行表观遗传调控的一种新机制。
