Kleinridders, A., Pogoda, H.M., Irlenbusch, S., Smyth, N., Koncz, C., Hammerschmidt, M., and Brüning, J.C. (2009) PLRG1 is an Essential Regulator of Cell Proliferation and Apoptosis during Vertebrate Development and Tissue Homeostasis. Molecular and cellular biology. 29(11):3173-3185.
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 inactivation of PLRG1 in mice results in embryonic lethality at 1.5 days post-fertilization. Studies on heart- and neuron-specific PLRG1 knockout mice further reveal an essential role of PLRG1 in adult tissue homeostasis and 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 gammaH2AX 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, deletion of PLRG1 results in relocation of its interaction partner CDC5L from the nucleus to the cytoplasm without general alterations in pre-mRNA splicing. Taken together, this study identifies PLRG1 as a critical nuclear regulator of p53-dependent cell cycle progression and apoptosis both during embryonic development and adult tissue homeostasis.