Proteasome Activator PA200 Is Required for Normal Spermatogenesis

Abstract

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^Δ) through Cre-loxP-mediated interchromosomal recombination after targeting loxP sites at either end of the locus. PA200^Δ/Δ 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^Δ/Δ mice. Additionally, PA200^Δ/Δ 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.

We thank Daniel Finley and Marion Schmidt for critical review of the manuscript.

This work is supported in part by National Institutes of Health grants AI47829 and AI47829 (B.P.S.) and American Cancer Society grant RSG-05-070-01-LIB (B.P.S.). C.H. is supported by a postdoctoral training grant from the NIH. Mice were produced by a transgenic core facility supported by the Rheumatic Diseases Core Center at Washington University (NIH P30-AR48335) and housed in a facility supported by NCRR grant RR012466.