title: TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21.
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 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences,  Xiamen University, Xiamen, Fujian 361005,  China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.forename: Nai-yang
authors.initials: NY
authors.lastname: Fu
authors.forename: Li
authors.initials: L
authors.lastname: Guan
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Hui-hui
authors.initials: HH
authors.lastname: Liu
authors.forename: Chun-dong
authors.initials: CD
authors.lastname: Yu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yu
authors.forename: Han
authors.initials: H
authors.lastname: You
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025801:Ubiquitin; C414583:TRIM39 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex