Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-03, Vol.108 (9), p.3624-3629
• Main Authors: Beyer, Ulrike, Moll-Rocek, Julian, Moll, Ute M, Dobbelstein, Matthias
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biological Sciences; Cell lines; Cells; DNA Damage; Endogenous Retroviruses - drug effects; Endogenous Retroviruses - metabolism; Evolution; Exons; Exons - genetics; Gene expression; Gene Expression Regulation - drug effects; Gene Silencing - drug effects; Germ cells; Histone Deacetylase Inhibitors - pharmacology; Hominidae; Hominidae - metabolism; Human endogenous retrovirus; Humans; Male; Messenger RNA; Molecular Sequence Data; Monkeys & apes; Mutagenesis, Insertional - genetics; Organ Specificity - drug effects; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Spermatozoa - drug effects; Spermatozoa - metabolism; Spermatozoa - pathology; Terminal Repeat Sequences - genetics; Testes; Testicular Neoplasms - enzymology; Testicular Neoplasms - pathology; Testis - drug effects; Testis - metabolism; Testis - pathology; Tissues; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors; Transcription, Genetic; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1016201108

TAp63, but not its homolog p53, eliminates oocytes that suffered DNA damage. An equivalent gene for guarding the male germ line is currently not known. Here we identify hitherto unknown human p63 transcripts with unique 5'-ends derived from incorporated exons upstream of the currently mapped TP63 gene. These unique p63 transcripts are highly and specifically expressed in testis. Their most upstream region corresponds to a LTR of the human endogenous retrovirus 9 (ERV9). The insertion of this LTR upstream of the TP63 locus occurred only recently in evolution and is unique to humans and great apes (Hominidae). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa. In response to DNA damage, this human male germ-cell-encoded TAp63 protein (designated GTAp63) is activated by caspase cleavage near its carboxyterminal domain and induces apoptosis. Human testicular cancer tissues and cell lines largely lost p63 expression. However, pharmacological inhibition of histone deacetylases completely restores p63 expression in testicular cancer cells (>3,000-fold increase). Our data support a model whereby testis-specific GTAp63 protects the genomic integrity of the male germ line and acts as a tumor suppressor. In Hominidae, this guardian function was greatly enhanced by integration of an endogenous retrovirus upstream of the TP63 locus that occurred 15 million years ago. By providing increased germ-line stability, this event may have contributed to the evolution of hominids and enabled their long reproductive periods.