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

Abstract

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-cellencoded 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.spermatogonia | genomic surveillance | primate evolution | seminoma | suberoylanilide hydroxamic acid

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“…Interestingly, transcription of LTR12-driven TNFRSF10B and TP63was enhanced by more than 1000-fold in testicular cancer cells upon treatment with the HDAC inhibitors (HDACi) Trichostatin A (TSA) as well as the structurally similar suberoylanilidehydroxamic acid (SAHA) [19,20]. Functionally, this enhanced LTR12 promoter activity resulted in elevated levels of the TNFRSF10B gene product, death receptor 5 (DR5), and testicular cancer cell death.…”

“…However, treatment with HDAC inhibitors results in strong derepression of the LTR12 promoter activity [19,20]. We now asked whether this mechanism is also accessible in tumor cells derived from tissues other than testis.…”

“…LTR12-driven transcription is present in normal testis, but silenced in testicular cancer cells [20]. However, treatment with HDAC inhibitors results in strong derepression of the LTR12 promoter activity [19,20].…”

“…Based on our previous observations that LTR12-driven gene transcription is strongly induced bythe hydroxamate HDAC inhibitors TSA and SAHA [19,20], we now tested a panel of HDAC inhibitors from different chemical classes as to their influence on LTR12 promoter activity. Testicular cancer-derived GH cells were treated with 0.5/2/8 µM of HDAC inhibitors for 18 h. Subsequently, the relative gene expression levels of LTR12-driven TP63 (GTAp63) and TNFRSF10B were assessed by qRT-PCR.…”

The DNA Damage Response in Mammalian Oocytes.

“…TAp63, a p63 isoform, is the only p53 family member identified so far to participate in the oocyte DDR. Although, TAp63 is not expressed in the male germ cells, a newly identified hominidae isoform, GTAp63, seems to possess DDR functions in males (Beyer et al, 2011;Amelio et al, 2012).…”