p63 the guardian of human reproduction

Abstract

p63 is a transcriptional factor implicated in cancer and development. The presence in TP63 gene of alternative promoters allows expression of one isoform containing the N-terminal transactivation domain (TA isoform) and one N-terminal truncated isoform (ΔN isoform). Complete ablation of all p63 isoforms produced mice with fatal developmental abnormalities, including lack of epidermal barrier, limbs and other epidermal appendages. Specific TAp63-null mice, although they developed normally, failed to undergo in DNA damage-induced apoptosis during primordial follicle meiotic arrest, suggesting a p63 involvement in maternal reproduction. Recent findings have elucidated the role in DNA damage response of a novel Hominidae p63 isoform, GTAp63, specifically expressed in human spermatic precursors. Thus, these findings suggest a unique strategy of p63 gene, to evolve in order to preserve the species as a guardian of reproduction. Elucidation of the biological basis of p63 function in reproduction may provide novel approaches to the control of human fertility.

Figure 1. Schematic representation of TAp63a’s switch from an inactive dimer to an active tetramer. Interactions within the TAp63a dimer maintain the transcriptional factor in an inactive form: the TA domain from one monomer respectively interacts with TI domain from opposite monomer. Phosphorylation is required to open dimers and allows interaction for tetramerizion. C-Abl is one of the kinases able to trigger activating phosphorylation. TA, transactivation domain; TI, transactivation inhibitory domain.

Figure 2. DNA damage actives oocyte death by triggering TAp63 phosphorylation. DNA damage leads to activation of TAp63 inducing its phosphorylation by different kinases. Activated TAp63 mediates the oocyte death by inducing transcription of BH3-only proapoptotic family members, PUMA and NOXA, which can inhibit pro-survival BCL-2 proteins (BCL-2, BCL-w, A1, MCL-1, BCL-XL).

Figure 3. Human testis-specific p63 isoforms are encoded by unique upstream exons. (A) Gene architecture of human p63 gene shows presence of unique upstream exons, U1, U2, U3 (sky-blue). The GTAp63 testis-specific isoform is encoded by a direct fusion of exon U1 to exon 2 by premRNA splicing. The black arrows indicate, starting from their first exons, the three transcriptional start sites for GTA (exon U1, sky blues), TA (exon 1, brown) and ΔN (exon 3′, gray). The downstream exons 10 and 14 undergo alternative splicing, encoding for the most abundant isoforms α and less abundant β and γ. The ERV9 LTR insert shows the transcriptional start site (TSS) of GTAp63. (B) N-terminal amino acid sequences of GTAp63 and TAp63. The 19-amino acidic long N-terminal of GTAp63 encoded by exon U1 is highlighted in green, while in blue is highlighted amino acid sequence codified by exon 2. Red “M” indicates Metionines at translational starts of GTAp63 or TAp63.