DNA damage induces the rapid and selective degradation of the ΔNp73 isoform, allowing apoptosis to occur

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p73 belongs to the family of transcription factors that also includes p53 and p63. The three proteins share a significant degree of sequence homology, and these structural similarities are paralleled by a certain degree of functional overlap and all members of the family are capable of inducing cell cycle arrest and apoptosis¹ (reviewed in reference Melino et al.²). Unlike p53, the p73 gene gives rise to a number of different mRNAs, which are translated into several different proteins. The different mRNAs arise either by alternative splicing or by the use of alternative promoters. Most of the splicing occurs at the 3′ end (isoforms α to η), in a part of the sequence that is not present in p53, and creates proteins that have different C-termini.^1,3,4,5,6 In addition, the second promoter (P2), located in intron 3, controls the expression of ΔNp73s. These N-terminally truncated isoforms lack the transactivation (TA) domain, but have novel sequence coded in an additional exon, exon 3′.⁷ Moreover, additional isoforms of p73 that lack the N-terminal TA domain can also arise from alternative splicing of transcripts originating from the first exon.^8,9,10 While TAp73 isoforms work as transcription factors, the ΔNp73 isoforms that lack the transactivation domain are incapable of directly inducing gene expression and do not induce growth arrest or cell death. However, the ΔNp73 forms have a very important regulatory role, since they exert a dominant negative effect on p53 and TAp73 by blocking their transactivation activity, and hence their ability to induce apoptosis.⁷ The relative levels of expression and more importantly the steady-state levels of the ΔNp73 isoforms can therefore determine the function of both TAp73 and p53. It is therefore most interesting that the ΔNp73 promoter (P2) contains a very efficient p53/p73 responsive element and consequently, p53 and TAp73 efficiently induce ΔNp73 expression.⁷ This creates a dominant negative feedback loop that regulates the function of both p53 and TAp73 and can fine tune the function of p53 (reviewed in Melino et al.²).

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