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Molecular and Cellular Biology, April 2006, p. 2999-3007, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2999-3007.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Proteasome Activator PA200 Is Required for Normal Spermatogenesis

Bernard Khor,1 Andrea L. Bredemeyer,1 Ching-Yu Huang,1 Isaiah R. Turnbull,1 Ryan Evans,1,{dagger} Leonard B. Maggi Jr.,1 J. Michael White,1 Laura M. Walker,1 Kay Carnes,2 Rex A. Hess,2 and Barry P. Sleckman1*

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63105,1 Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 618022

Received 21 November 2005/ Returned for modification 28 January 2006/ Accepted 30 January 2006

The PA200 proteasome activator is a broadly expressed nuclear protein. Although how PA200 normally functions is not fully understood, it has been suggested to be involved in the repair of DNA double-strand breaks (DSBs). The PA200 gene (Psme4) is composed of 45 coding exons spanning 108 kb on mouse chromosome 11. We generated a PA200 null allele (PA200{Delta}) through Cre-loxP-mediated interchromosomal recombination after targeting loxP sites at either end of the locus. PA200{Delta}/{Delta} mice are viable and have no obvious developmental abnormalities. Both lymphocyte development and immunoglobulin class switching, which rely on the generation and repair of DNA DSBs, are unperturbed in PA200{Delta}/{Delta} mice. Additionally, PA200{Delta}/{Delta} embryonic stem cells do not exhibit increased sensitivity to either ionizing radiation or bleomycin. Thus, PA200 is not essential for the repair of DNA DSBs generated in these settings. Notably, loss of PA200 led to a marked reduction in male, but not female, fertility. This was due to defects in spermatogenesis observed in meiotic spermatocytes and during the maturation of postmeiotic haploid spermatids. Thus, PA200 serves an important nonredundant function during spermatogenesis, suggesting that the efficient generation of male gametes has distinct protein metabolic requirements.

* Corresponding author. Mailing address: Department of Pathology and Immunology, 660 S. Euclid Ave., Campus Box 8118, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 747-8235. Fax: (314) 362-4096. E-mail: Sleckman{at}immunology.wustl.edu.

{dagger} Present address: Program in Biomedical Sciences, University of Michigan, Ann Arbor, MI 48109-0619.

Molecular and Cellular Biology, April 2006, p. 2999-3007, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2999-3007.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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