State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20937-42. doi: 10.1073/pnas.1214156110. Epub 2012 Dec 4.
The biological function of Tripartite Motif 39 (TRIM39) remains largely unknown. In this study, we report that TRIM39 regulates the steady-state levels of p21 and is a pivotal determinant of cell fate. Ablation of TRIM39 leads to destabilization of p21 and increased G1/S transition in unperturbed cells. Furthermore, DNA damage-induced p21 accumulation is completely abolished in cells with depleted TRIM39. As a result, silencing of TRIM39 abrogates the G2 checkpoint induced by genotoxic stress, leading to increased mitotic entry and, ultimately, apoptosis. Importantly, we show p21 is a crucial downstream effector of TRIM39 mediating G1/S transition and DNA damage-induced G2 arrest. Mechanistically, TRIM39 interacts with p21, which subsequently prevents Cdt2 from binding to p21, therefore blocking ubiquitylation and proteasomal degradation of p21 mediated by CRL4(Cdt2) E3 ligase. Strikingly, we found a significant correlation between p21 abundance and TRIM39 expression levels in human hepatocellular carcinoma samples. Our findings identify a causal role for TRIM39 in regulating cell cycle progression and the balance between cytostasis and apoptosis after DNA damage via stabilizing p21.
TRIM39 的生物学功能在很大程度上仍然未知。在这项研究中，我们报告称 TRIM39 调节 p21 的稳定水平，是细胞命运的关键决定因素。TRIM39 的缺失导致 p21 的不稳定性增加，并在未受干扰的细胞中增加 G1/S 转换。此外，DNA 损伤诱导的 p21 积累在 TRIM39 耗尽的细胞中完全被消除。结果，沉默 TRIM39 消除了由遗传毒性应激诱导的 G2 检查点，导致有丝分裂进入增加，最终导致细胞凋亡。重要的是，我们表明 p21 是介导 G1/S 转换和 DNA 损伤诱导的 G2 阻滞的 TRIM39 的关键下游效应子。在机制上，TRIM39 与 p21 相互作用，随后阻止 Cdt2 与 p21 结合，从而阻止 CRL4(Cdt2)E3 连接酶介导的 p21 的泛素化和蛋白酶体降解。引人注目的是，我们在人肝癌样本中发现 p21 丰度与 TRIM39 表达水平之间存在显著相关性。我们的发现确定了 TRIM39 通过稳定 p21 在调节细胞周期进程以及 DNA 损伤后细胞静止和细胞凋亡之间的平衡方面的因果作用。
