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|Title:||TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21|
|Citation:||Zhang, L., Mei, Y., Fu, N.-Y., Guan, L., Xie, W., Liu, H.-H., Yu, C.-D., Yin, Z., Yu, V.C., You, H. (2012-12-18). TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21. Proceedings of the National Academy of Sciences of the United States of America 109 (51) : 20937-20942. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.1214156110|
|Abstract:||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 CRL4Cdt2 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.|
|Source Title:||Proceedings of the National Academy of Sciences of the United States of America|
|Appears in Collections:||Staff Publications|
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