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J. Biol. Chem., Vol. 282, Issue 52, 37359-37369, December 28, 2007

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Mammalian Gene PEG10 Expresses Two Reading Frames by High Efficiency –1 Frameshifting in Embryonic-associated Tissues^*

From the Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand

Paternally expressed gene 10 (PEG10) is a mammalian gene that is essential for embryonic development in mice. The gene contains two overlapping open reading frames (ORF1 and ORF2) and is derived from a retroelement that acquired a cellular function. It is not known if both reading frames are required for PEG10 function. Synthesis of ORF2 would be possible only if programmed –1 frameshifting occurred during ORF1 translation. In this study the frameshifting activity of PEG10 was analyzed in vivo, and a potential role for ORF2 was investigated. Phylogenetic analysis demonstrated that PEG10 is highly conserved in therian mammals, with all species retaining the elements necessary for frameshifting as well as functional motifs in each ORF. The frameshift site of PEG10 was highly active in cultured cells and produced the ORF1-2 protein. In mice, endogenous ORF1 and an ORF1-2 frameshift protein were detected in the developing placenta and amniotic membrane from 9.5 days post-coitus through to term with a very high frameshift efficiency (>60%). Mutagenesis of the active site motif of a putative protease within ORF2 showed that this enzyme is active and participates in post-translational processing of PEG10 ORF1-2. Both PEG10 proteins were also detected in first trimester human placenta. By contrast, neither protein expression nor frameshifting was detected in adult mouse tissues. These studies imply that the ORF1-2 protein, synthesized utilizing the most efficient –1 frameshift mechanism yet documented in vivo, will have an essential function that is intrinsic to the importance of PEG10 in mammals.

Received for publication, July 11, 2007 , and in revised form, October 10, 2007.

^* This work was supported by grants from the Otago Medical Research Foundation and the Health Research Council of New Zealand (to W. P. T. and E. S. P.), the University of Otago Research Committee (to W. P. T.), and University of Otago for masters scholarships (to M. C. and M. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Table 1.

¹ The first two authors were major contributors to the studies described in this manuscript.

² Present address: Max Planck Institute of Immunobiology, Freiburg D-79108, Germany.

³ Present address: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.

⁴ To whom correspondence should be addressed: Dept. of Biochemistry, University of Otago, P. O. Box 56, Dunedin 9054, New Zealand. Tel.: 64-3-479-7839; Fax: 64-3-479-7866; E-mail: warren.tate{at}stonebow.otago.ac.nz.

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