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Molecular and Cellular Biology, March 2008, p. 1503-1514, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01565-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

ARS2 Is a Conserved Eukaryotic Gene Essential for Early Mammalian Development ^,

Michael D. Wilson,^1,2, Diana Wang,^1,2,3 Rebecca Wagner,¹ Hilde Breyssens,⁴ Marina Gertsenstein,⁵ Corrinne Lobe,⁶ Xin Lu,⁴ Andras Nagy,⁵ Robert D. Burke,^1,2,3 Ben F. Koop,^1,2* and Perry L. Howard^1,2,3*

Centre for Biomedical Research, University of Victoria, Victoria, British Columbia, Canada,¹ Department of Biology, University of Victoria, Victoria, British Columbia, Canada,² Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia Canada,³ Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom,⁴ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada,⁵ Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada⁶

Received 26 August 2007/ Returned for modification 25 September 2007/ Accepted 7 December 2007

Determining the functions of novel genes implicated in cell survival is directly relevant to our understanding of mammalian development and carcinogenesis. ARS2 is an evolutionarily conserved gene that confers arsenite resistance on arsenite-sensitive Chinese hamster ovary cells. Little is known regarding the function of ARS2 in mammals. We report that ARS2 is transcribed throughout embryonic development and is expressed ubiquitously in mouse and human tissues. The mouse ARS2 protein is predominantly localized to the nucleus, and this nuclear localization is ablated in ARS2-null embryos, which in turn die around the time of implantation. After 24 h of culture, ARS2-null blastocysts contained a significantly greater number of apoptotic cells than wild-type or heterozygous blastocysts. By 48 h of in vitro culture, null blastocysts invariably collapsed and failed to proliferate. These data indicate ARS2 is essential for early mammalian development and is likely involved in an essential cellular process. The analysis of data from several independent protein-protein interaction studies in mammals, combined with functional studies of its Arabidopsis ortholog, SERRATE, suggests that this essential process is related to RNA metabolism.

Published ahead of print on 17 December 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom.