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

Kwon, Yong Tae and Xia, Zanxian and An, Jee Young and Tasaki, Takafumi and Davydov, Ilia V. and Seo, Jai Wha and Sheng, Jun and Xie, Youming and Varshavsky, Alexander (2003) Female Lethality and Apoptosis of Spermatocytes in Mice Lacking the UBR2 Ubiquitin Ligase of the N-End Rule Pathway. Molecular and Cellular Biology, 23 (22). pp. 8255-8271. ISSN 0270-7306. PMCID PMC262401. doi:10.1128/MCB.23.22.8255-8271.2003.

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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 E3α, 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.

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Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2003, American Society for Microbiology. Received 5 June 2003/Returned for modification 21 July 2003/Accepted 5 August 2003 Z. Xia and J. Y. An contributed equally to this work. We are grateful to members of the Caltech Transgenic and Knockout Core Facility, especially S. Pease, B. Kennedy, and L. Sandoval, for care of mice and expert technical help. We thank F. Du (Yale University, New Haven, Conn.) for a precursor of SSC1-encoding plasmids of the present study; W. Baarends (Erasmus University) for anti-tH2B, anti-TP2, and advice; C. Höög (Karolinska Institute) for anti-SCP3 and the CREST serum; P. Moens (York University) for anti-SCP3; and H.P. Roest (Erasmus University) for anti-HR6B. This work was supported by the NIH grants GM31530 and DK39520 and by a grant from the Kirsch Foundation to A.V.
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Kirsch FoundationUNSPECIFIED
Issue or Number:22
PubMed Central ID:PMC262401
Record Number:CaltechAUTHORS:KWOmcb03
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Official Citation:Female Lethality and Apoptosis of Spermatocytes in Mice Lacking the UBR2 Ubiquitin Ligase of the N-End Rule Pathway Yong Tae Kwon, Zanxian Xia, Jee Young An, Takafumi Tasaki, Ilia V. Davydov, Jai Wha Seo, Jun Sheng, Youming Xie, and Alexander Varshavsky Mol. Cell. Biol. November 2003 23:22 8255-8271; doi:10.1128/MCB.23.22.8255-8271.2003
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6831
Deposited By: Archive Administrator
Deposited On:23 Dec 2006
Last Modified:08 Nov 2021 20:37

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