Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
Oncogene. 2012 Sep 27;31(39):4290-301. doi: 10.1038/onc.2011.605. Epub 2012 Jan 16.
Linker histone H1.2 has been shown to suppress p53-dependent transcription through the modulation of chromatin remodeling; however, little is known about the mechanisms governing the antagonistic effects of H1.2 in DNA damage response. Here, we show that the repressive action of H1.2 on p53 function is negatively regulated via acetylation of p53 C-terminal regulatory domain and phosphorylation of H1.2 C-terminal tail. p53 acetylation by p300 impairs the interaction of p53 with H1.2 and triggers a rapid activation of p53-dependent transcription. Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. Consistent with these findings, point mutations mimicking modification states of H1.2 and p53 lead to a significant increase in p53-induced apoptosis. These data suggest that p53 acetylation-H1.2 phosphorylation cascade serves as a unique mechanism for triggering p53-dependent DNA damage response pathways.
组蛋白 H1.2 已被证实可通过调节染色质重塑来抑制 p53 依赖性转录；然而，对于 H1.2 在 DNA 损伤反应中拮抗作用的调控机制，我们知之甚少。在这里，我们发现 H1.2 对 p53 功能的抑制作用是通过 p53 C 端调节域的乙酰化和 H1.2 C 端尾部的磷酸化来负调控的。p300 介导的 p53 乙酰化会损害 p53 与 H1.2 的相互作用，并触发 p53 依赖性转录的快速激活。类似地，DNA-PK 介导的 H1.2 在 T146 位的磷酸化通过阻碍 H1.2 与 p53 的结合，从而削弱其对 p53 反式激活的抑制作用，增强了 p53 的转录活性。与这些发现一致，模拟 H1.2 和 p53 修饰状态的点突变导致 p53 诱导的细胞凋亡显著增加。这些数据表明，p53 乙酰化-H1.2 磷酸化级联反应是触发 p53 依赖性 DNA 损伤反应途径的独特机制。
