Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis

• Published in: Current biology 2012-03, Vol.22 (5), p.420-425
• Main Authors: Chen, Dong, Zheng, Wei, Lin, Aiping, Uyhazi, Katherine, Zhao, Hongyu, Lin, Haifan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Cell cycle; Cell Cycle - genetics; Fertility; Germ cells; Homeostasis; Male; MAP kinase; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; mRNA; Oligospermia; operon; Operons; p53 protein; Post-transcription; RNA; RNA Processing, Post-Transcriptional - physiology; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal transduction; Sperm; Sperm Count; Spermatocytes; Spermatogenesis; Spermatogenesis - physiology; spermatozoa; Spermatozoa - cytology; Spermatozoa - metabolism; Testes; Testis - cytology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2012.01.039

During spermatogenesis, germ cells initially expand exponentially through mitoses. A majority of these cells are then eliminated through p53-mediated apoptosis to maintain germline homeostasis [1–4]. However, the activity of p53 must be precisely modulated, especially suppressed in postmitotic spermatogenic cells, to guarantee robustness of spermatogenesis. Currently, how the suppression is achieved is not understood. Here, we show that Pumilio 1, a posttranscriptional regulator, binds to mRNAs representing 1,527 genes, with significant enrichment for mRNAs involved in pathways regulating p53, cell cycle, and MAPK signaling. In particular, eight mRNAs encoding activators of p53 are repressed by Pumilio 1. Deleting Pumilio 1 results in strong activation of p53 and apoptosis mostly in spermatocytes, which disrupts sperm production and fertility. Removing p53 reduces apoptosis and rescues testicular hypotrophy in Pumilio 1 null mice. These results indicate that key components of the p53 pathway are coordinately regulated by Pumilio 1 at the posttranscriptional level, which may exemplify an RNA operon. ► Pum1 null males have significantly reduced sperm count and fertility ► Pum1 null testes display elevated apoptosis in spermatocytes ► Among its other target mRNAs, Pum1 binds to and represses multiple activators of p53 ► p53 deficiency rescues Pum1 phenotype