Kurash Julia K, Lei Hong, Shen Qiong, Marston Wendy L, Granda Brian W, Fan Hong, Wall Daniel, Li En, Gaudet François
Epigenetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
Mol Cell. 2008 Feb 15;29(3):392-400. doi: 10.1016/j.molcel.2007.12.025.
The protein methyltransferase Set7/9 was recently shown to regulate p53 activity in cancer cells. However, the impact of Set7/9 on p53 function in vivo is unclear. To explore these issues, we created a null allele of Set7/9 in mice. Cells from Set7/9 mutant mice fail to methylate p53 K369, are unable to induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Importantly, we find that methylation of p53 by Set7/9 is required for the binding of the acetyltransferase Tip60 to p53 and for the subsequent acetylation of p53. We provide the first genetic evidence demonstrating that lysine methylation of p53 by Set7/9 is important for p53 activation in vivo and suggest a mechanistic link between methylation and acetylation of p53 through Tip60.
蛋白甲基转移酶Set7/9最近被证明可调节癌细胞中的p53活性。然而，Set7/9在体内对p53功能的影响尚不清楚。为了探究这些问题，我们在小鼠中创建了Set7/9的无效等位基因。Set7/9突变小鼠的细胞无法使p53 K369甲基化，在DNA损伤时无法诱导p53下游靶点，并且易于发生致癌转化。重要的是，我们发现Set7/9对p53的甲基化是乙酰转移酶Tip60与p53结合以及随后p53乙酰化所必需的。我们提供了首个遗传学证据，证明Set7/9对p53的赖氨酸甲基化在体内对p53激活很重要，并提出了通过Tip60实现p53甲基化和乙酰化之间的机制联系。
