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p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression, Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative ANp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and ANp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or ANp73 resulted in an increase of the TA/ANp73 ratio, due to preferential degradation of ANp73. Finally, PIR2 was able to relieve the inhibitory effect of ANp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading ANp73, differentially regulates TAp73/ANp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells. p73 | RNF144b | ubiquitylation | DNA damage doi/ 10.1073/pnas.0911828107