現(xiàn)有的研究揭示TRIM（tripartite motif）家族的成員在調(diào)節(jié)細(xì)胞凋亡,、細(xì)胞周期中有重要作用,，并且與遺傳性疾病,，神經(jīng)系統(tǒng)異常以及癌癥等都有著密切的關(guān)系。TRIM39自2000年被克隆,，其生物學(xué)功能一直是個謎,。p21是一個細(xì)胞周期蛋白依賴性激酶的抑制分子，它通過調(diào)控細(xì)胞周期的進(jìn)程,，參與細(xì)胞生長,、分化,、衰老和死亡的調(diào)節(jié)，在細(xì)胞應(yīng)對應(yīng)激刺激以及腫瘤的發(fā)生發(fā)展中,，發(fā)揮重要的作用,。研究發(fā)現(xiàn)TRIM39與p21相互作用，從而阻止CRL4Cdt2這個E3復(fù)合物中的底物識別蛋白Cdt2與p21的結(jié)合,，進(jìn)而抑制CRL4Cdt2E3復(fù)合物介導(dǎo)的對p21的泛素化---蛋白酶體降解,，由此影響細(xì)胞周期以及細(xì)胞對DNA損傷刺激的應(yīng)答。本研究揭示了TRIM39是調(diào)控細(xì)胞周期的重要分子,，在生理狀態(tài)下TRIM39負(fù)向調(diào)控細(xì)胞周期進(jìn)程,，在DNA損傷刺激條件下，TRIM39對細(xì)胞周期停滯起至關(guān)重要的作用,，研究的研究還進(jìn)一步闡明TRIM39家族分子之間存在相互作用,，共同調(diào)節(jié)p21蛋白穩(wěn)定性，從而為進(jìn)一步了解p21在細(xì)胞中的精確調(diào)控機(jī)制和在分子基因水平進(jìn)行腫瘤治療提供重要的理論依據(jù),。
生命科學(xué)學(xué)院張蕾博士為本文的第一作者,，尤涵教授是本文的通訊作者，合作單位包括中山醫(yī)院肝膽外科,，以及新加坡國立大學(xué),。此項研究受到國家自然科學(xué)基金委和科技部資助。（生物谷Bioon.com）
doi: 10.1073/pnas.1214156110
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PMID:
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.
