Δ113p53/Δ133p53: survival and integrity

In 2005, two reports, one on analysis of 5'-RACE PCR products of p53 transcripts in human normal tissues [1] and the other on analysis of a zebrafish genetic mutant def hi429 [2], described the discovery of p53 isoforms. Since then it has raised tremendous interest in the cancer research community to unravel the function and regulation of these isoforms due to the fact that p53 (TP53) is the most important tumor suppressor. During last ten years, main focus has been put on studying one unique type of p53 isoforms, namely the zebrafish ∆113p53 and its human counterpart ∆133p53, both are transcribed by an alternative p53 promoter in intron 4 and encodes N-terminal truncated forms of p53 [3]. In summary, these studies demonstrated that ∆113p53/∆133p53 are p53 target genes and function to antagonize p53's apoptotic function or to inhibit cell replicative senescence [1, 3, 4 ,5]. Recently, four zebrafish p53 isoforms, namely TA2/3/4/5p53 were identified. These isoforms are derived from a naturally occurring 4 bp genomic deletion in the intron 1 of the Δ113p53 gene (part of the intron 4 of the p53 gene) [6]. All of these new isoforms also promote embryo survival by repressing apoptosis upon γ-irradiation [6]. DNA double strand breaks (DSB) are the most deleterious DNA lesions that a cell can encounter. To combat these detrimental insults, three pathways have evolved for the repair of DSB: Homologous Recombination (HR), Non-Homologous End Joining (NHEJ) and Single-Strand Annealing (SSA). It is well established that full-length p53 represses DNA DSB repair by either preventing repair complex formation through interacting with several essential HR-related proteins such as RAD51 and RPA, or transcriptionally suppressing the expression of DNA DSB repair genes e.g. RAD51, RECQ4 and WRN [7]. This is consistent with the observation that p53 protein is rapidly accumulated to a high level in response to DNA DSB stress at early stage. However, activated p53 also activates the expression of MDM2, an E3 ligase that mediates the degradation of p53 at the later stage. Therefore, it is of great interest to understand the role of the activated p53 signal pathway in response to DNA DSB stress at the later stage. We showed previously that, in response to DNA damage, ∆113p53/∆133p53 is strongly induced to antagonizes p53 apoptotic activity specifically [3]. We asked whether p53 isoforms are involved in the DNA DSB repair. Our study, recently published in Cell Research, demonstrates that in …