Kleinridders André, Pogoda Hans-Martin, Irlenbusch Sigrid, Smyth Neil, Koncz Csaba, Hammerschmidt Matthias, Brüning Jens C
Institute for Genetics, Department of Mouse Genetics and Metabolism, University of Cologne, Cologne, Germany.
Mol Cell Biol. 2009 Jun;29(11):3173-85. doi: 10.1128/MCB.01807-08. Epub 2009 Mar 23.
PLRG1, an evolutionarily conserved component of the spliceosome, forms a complex with Pso4/SNEV/Prp19 and the cell division and cycle 5 homolog (CDC5L) that is involved in both pre-mRNA splicing and DNA repair. Here, we show that the inactivation of PLRG1 in mice results in embryonic lethality at 1.5 days postfertilization. Studies of heart- and neuron-specific PLRG1 knockout mice further reveal an essential role of PLRG1 in adult tissue homeostasis and the suppression of apoptosis. PLRG1-deficient mouse embryonic fibroblasts (MEFs) fail to progress through S phase upon serum stimulation and exhibit increased rates of apoptosis. PLRG1 deficiency causes enhanced p53 phosphorylation and stabilization in the presence of increased gamma-H2AX immunoreactivity as an indicator of an activated DNA damage response. p53 downregulation rescues lethality in both PLRG1-deficient MEFs and zebrafish in vivo, showing that apoptosis resulting from PLRG1 deficiency is p53 dependent. Moreover, the deletion of PLRG1 results in the relocation of its interaction partner CDC5L from the nucleus to the cytoplasm without general alterations in pre-mRNA splicing. Taken together, the results of this study identify PLRG1 as a critical nuclear regulator of p53-dependent cell cycle progression and apoptosis during both embryonic development and adult tissue homeostasis.
PLRG1是剪接体中一种进化上保守的成分，它与Pso4/SNEV/Prp19以及细胞分裂周期5同源物（CDC5L）形成复合物，参与前体mRNA剪接和DNA修复。在此，我们表明小鼠中PLRG1的失活导致受精后1.5天胚胎致死。对心脏和神经元特异性PLRG1基因敲除小鼠的研究进一步揭示了PLRG1在成体组织稳态和细胞凋亡抑制中的重要作用。PLRG1缺陷的小鼠胚胎成纤维细胞（MEF）在血清刺激后无法进入S期，并表现出凋亡率增加。PLRG1缺陷导致p53磷酸化增强和稳定性增加，同时γ-H2AX免疫反应性增加，作为DNA损伤反应激活的指标。p53下调挽救了PLRG1缺陷的MEF和斑马鱼体内的致死性，表明PLRG1缺陷导致的细胞凋亡是p53依赖性的。此外，PLRG1的缺失导致其相互作用伴侣CDC5L从细胞核重新定位到细胞质，而前体mRNA剪接没有普遍改变。综上所述，本研究结果确定PLRG1是胚胎发育和成体组织稳态过程中p53依赖性细胞周期进程和细胞凋亡的关键核调节因子。
