Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Cell Death Differ. 2013 Apr;20(4):620-9. doi: 10.1038/cdd.2012.159. Epub 2012 Dec 14.
The molecular mechanisms controlling post-translational modifications of p21 have been pursued assiduously in recent years. Here, utilizing mass-spectrometry analysis and site-specific acetyl-p21 antibody, two lysine residues of p21, located at amino-acid sites 161 and 163, were identified as Tip60-mediated acetylation targets for the first time. Detection of adriamycin-induced p21 acetylation, which disappeared after Tip60 depletion with concomitant destabilization of p21 and disruption of G1 arrest, suggested that Tip60-mediated p21 acetylation is necessary for DNA damage-induced cell-cycle regulation. The ability of 2KQ, a mimetic of acetylated p21, to induce cell-cycle arrest and senescence was significantly enhanced in p21 null MEFs compared with those of cells expressing wild-type p21. Together, these observations demonstrate that Tip60-mediated p21 acetylation is a novel and essential regulatory process required for p21-dependent DNA damage-induced cell-cycle arrest.
近年来，人们一直在深入研究控制 p21 翻译后修饰的分子机制。在这里，我们利用质谱分析和特异性乙酰化 p21 抗体，首次鉴定出 p21 的两个赖氨酸残基，位于氨基酸位点 161 和 163，是 Tip60 介导的乙酰化靶标。检测阿霉素诱导的 p21 乙酰化，在用 Tip60 耗尽伴随 p21 不稳定和 G1 阻滞破坏后消失，表明 Tip60 介导的 p21 乙酰化对于 DNA 损伤诱导的细胞周期调节是必要的。与表达野生型 p21 的细胞相比，2KQ（乙酰化 p21 的模拟物）在 p21 缺失 MEF 中诱导细胞周期停滞和衰老的能力显著增强。这些观察结果表明，Tip60 介导的 p21 乙酰化是 p21 依赖性 DNA 损伤诱导的细胞周期阻滞所必需的一种新型和必要的调节过程。
