ZFY:A putative transcription factor with a poorly conserved N-terminus and a highly conserved C-terminus

ZFY is a male specific Y chromosome transcriptional factor with two splice variants: a long form that is ubiquitously expressed in most mammalian species, and a short form that is testis specific. Mouse models indicate that the physiological functions of full length ZFY include promoting meiotic sex chromosome silencing at the onset of pachytene, apoptotic elimination of aberrant cells during pachytene, and spermatid development following meiotic divisions. The testis specific short isoform has no known physiological role but is unable to activate transcription in Saccharomyces cerevisiae. Previous work in the Ellis-Fenton laboratory showed ectopic expression of the short form in HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) cell lines, which could reveal the factor leading to higher head and neck squamous cell carcinoma incidences in males than females. However, the mechanisms leading to the difference in the transactivating activity between the two isoforms are still unknown. Thus, we sought to locate the regions responsible for the transactivation activity of full length ZFY by performing protein and bioinformatic structural studies. We successfully expressed the testis specific short ZFY, and bioinformatically identified a conserved nine amino acid transactivation domain (9aa TAD) motif SVVIQDVVEDVVIE within the alternatively spliced exon. Our results suggest that short form ZFY may competitively bind to the same genomic sites as the full length ZFY, but lacks the motif predicted to recruit the core transcription complex. Thus, it may have an oncogenic effect due to inhibition of the pro-apoptotic functions of full length ZFY.