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Female Lethality and Apoptosis of Spermatocytes in Mice Lacking the UBR2 Ubiquitin Ligase of the N-End Rule Pathway

Yong Tae Kwon,^1* Zanxian Xia,² Jee Young An,¹ Takafumi Tasaki,¹ Ilia V. Davydov,^2, Jai Wha Seo,¹ Jun Sheng,² Youming Xie,^2, and Alexander Varshavsky²

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,¹ Division of Biology, California Institute of Technology, Pasadena, California 91125²

Received 5 June 2003/ Returned for modification 21 July 2003/ Accepted 5 August 2003

Substrates of the ubiquitin-dependent N-end rule pathway include proteins with destabilizing N-terminal residues. UBR1^-/- mice, which lacked the pathway's ubiquitin ligase E3, were viable and retained the N-end rule pathway. The present work describes the identification and analysis of mouse UBR2, a homolog of UBR1. We demonstrate that the substrate-binding properties of UBR2 are highly similar to those of UBR1, identifying UBR2 as the second E3 of the mammalian N-end rule pathway. UBR2^-/- mouse strains were constructed, and their viability was found to be dependent on both gender and genetic background. In the strain 129 (inbred) background, the UBR2^-/- genotype was lethal to most embryos of either gender. In the 129/B6 (mixed) background, most UBR2^-/- females died as embryos, whereas UBR2^-/- males were viable but infertile, owing to the postnatal degeneration of the testes. The gross architecture of UBR2^-/- testes was normal and spermatogonia were intact as well, but UBR2^-/- spermatocytes were arrested between leptotene/zygotene and pachytene and died through apoptosis. A conspicuous defect of UBR2^-/- spermatocytes was the absence of intact synaptonemal complexes. We conclude that the UBR2 ubiquitin ligase and, hence, the N-end rule pathway are required for male meiosis and spermatogenesis and for an essential aspect of female embryonic development.

Present address: IGEN, Inc., Gaithersburg, MD 20877.

Present address: Department of Pathology, School of Medicine, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201.

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