Previous Article | Next Article 
Molecular and Cellular Biology, June 2009, p. 3173-3185, Vol. 29, No. 11
0270-7306/09/$08.00+0 doi:10.1128/MCB.01807-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
PLRG1 Is an Essential Regulator of Cell Proliferation and Apoptosis during Vertebrate Development and Tissue Homeostasis
,
André Kleinridders,1,2,3,4*
Hans-Martin Pogoda,5
Sigrid Irlenbusch,1
Neil Smyth,6,7
Csaba Koncz,8,9
Matthias Hammerschmidt,5 and
Jens C. Brüning1,2,3,4
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), D-50674 Cologne, Germany,1 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), D-50674 Cologne, Germany,2 Max Planck Institute for the Biology of Ageing, D-50931 Cologne, Germany,3 Second Department for Internal Medicine, University Hospital Cologne, D-50931 Cologne, Germany,4 Institute for Developmental Biology, University of Cologne, D-50674 Cologne, Germany,5 Center for Biochemistry, University of Cologne, D-50674 Cologne, Germany,6 School of Biological Sciences, University of Southampton, Southampton SO16 7PX, United Kingdom,7 Max Planck Institute for Plant Breeding Research, D-50829 Cologne, Germany,8 Institute of Plant Biology, Biological Research Center of Hungarian Academy, H-6723 Szeged, Hungary9
Received 26 November 2008/ Returned for modification 31 December 2008/ Accepted 16 March 2009
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 
-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.
* Corresponding author. Mailing address: Institute for Genetics, Department of Mouse Genetics and Metabolism, Zülpicher Straße 47, 50674 Cologne, Germany. Phone: 49-221 470 2467. Fax: 49-221 470 5185. E-mail: jens.bruening{at}uni-koeln.de
Published ahead of print on 23 March 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, June 2009, p. 3173-3185, Vol. 29, No. 11
0270-7306/09/$08.00+0 doi:10.1128/MCB.01807-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»