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Molecular and Cellular Biology, February 2008, p. 1136-1146, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01566-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Mouse Polyubiquitin Gene Ubb Is Essential for Meiotic Progression ^,

Kwon-Yul Ryu,¹ Shamim A. Sinnar,¹ Laura G. Reinholdt,² Sergio Vaccari,³ Susan Hall,⁴ Manuel A. Garcia,⁵ Tatiana S. Zaitseva,¹ Donna M. Bouley,⁵ Kim Boekelheide,⁴ Mary Ann Handel,² Marco Conti,³ and Ron R. Kopito^1*

Department of Biological Sciences, Bio-X Program, Stanford University, Stanford, California 94305,¹ The Jackson Laboratory, Bar Harbor, Maine 04609,² Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University, Stanford, California 94305,³ Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912,⁴ Department of Comparative Medicine, Stanford University, Stanford, California 94305⁵

Received 27 August 2007/ Returned for modification 5 October 2007/ Accepted 12 November 2007

Ubiquitin is encoded in mice by two polyubiquitin genes, Ubb and Ubc, that are considered to be stress inducible and two constitutively expressed monoubiquitin (Uba) genes. Here we report that targeted disruption of Ubb results in male and female infertility due to failure of germ cells to progress through meiosis I and hypogonadism. In the absence of Ubb, spermatocytes and oocytes arrest during meiotic prophase, before metaphase of the first meiotic division. Although cellular ubiquitin levels are believed to be maintained by a combination of functional redundancy among the four ubiquitin genes, stress inducibility of the two polyubiquitin genes, and ubiquitin recycling by proteasome-associated isopeptidases, our results indicate that ubiquitin is required for and consumed during meiotic progression. The striking similarity of the meiotic phenotype in Ubb^–/– germ cells to the sporulation defect in fission yeast (Schizosaccharomyces pombe) lacking a polyubiquitin gene suggests that a meiotic role of the polyubiquitin gene has been conserved throughout eukaryotic evolution.

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* Corresponding author. Mailing address: Stanford University, Gilbert Room 304A, Mail Code 5020, Stanford, CA 94305. Phone: (650) 723-7581. Fax: (650) 724-9945. E-mail: kopito{at}stanford.edu

Published ahead of print on 10 December 2007.

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

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Molecular and Cellular Biology, February 2008, p. 1136-1146, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01566-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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