现有的研究揭示TRIM（tripartite motif）家族的成员在调节细胞凋亡、细胞周期中有重要作用，并且与遗传性疾病，神经系统异常以及癌症等都有着密切的关系。TRIM39自2000年被克隆，其生物学功能一直是个谜。p21是一个细胞周期蛋白依赖性激酶的抑制分子，它通过调控细胞周期的进程，参与细胞生长、分化、衰老和死亡的调节，在细胞应对应激刺激以及肿瘤的发生发展中，发挥重要的作用。研究发现TRIM39与p21相互作用，从而阻止CRL4Cdt2这个E3复合物中的底物识别蛋白Cdt2与p21的结合，进而抑制CRL4Cdt2E3复合物介导的对p21的泛素化---蛋白酶体降解，由此影响细胞周期以及细胞对DNA损伤刺激的应答。本研究揭示了TRIM39是调控细胞周期的重要分子，在生理状态下TRIM39负向调控细胞周期进程，在DNA损伤刺激条件下，TRIM39对细胞周期停滞起至关重要的作用，研究的研究还进一步阐明TRIM39家族分子之间存在相互作用，共同调节p21蛋白稳定性，从而为进一步了解p21在细胞中的精确调控机制和在分子基因水平进行肿瘤治疗提供重要的理论依据。
生命科学学院张蕾博士为本文的第一作者，尤涵教授是本文的通讯作者，合作单位包括中山医院肝胆外科，以及新加坡国立大学。此项研究受到国家自然科学基金委和科技部资助。（生物谷Bioon.com）
doi: 10.1073/pnas.1214156110
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TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21
Zhang L, Mei Y, Fu NY, Guan L, Xie W, Liu HH, Yu CD, Yin Z, Yu VC, You H.
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.
