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The p53 tumor suppressor is an essential barrier against cancer, which is evidenced by loss of p53 activity in the majority of human cancers and unexceptionally early onset of tumors in p53-knockout mice and human Li-Fraumeni syndrome patients. p53 is a sequence-specific transcription factor that regulates gene expression via binding to the consensus p53-responsive element (p53-RE). p53 acts as a central sig-naling coordinator that receives upstream signals, including DNA damage, aberrant oncogenic activity, hypoxia and ribosomal stress, and consequently activates its tar-gets leading to downstream cellular out-comes, including cell cycle arrest, DNA repair, apoptosis and cellular senescence. However, it is not yet clear how p53 dic-tates a cell to survival vs. death in response to a specific stress. It has been shown that the ability of p53 to regulate target genes can be modu-lated by posttranslational modifications. For example, acetylation of p53 on lysine 120 by Tip60 is crucial for p53-medi-ated apoptosis but not cell cycle arrest.1 Consistently, p90, a cofactor of Tip60, is required for Tip60-dependent p53 acety-lation and, thus, specifically promotes p53-mediated apoptosis.2 Interestingly, evidence showed that p53 activity is also regulated by binding partners that do not affect p53 modifications. For exam-ple, ASPP proteins interact with p53 and enhance the DNA binding and transacti-vation function of p53 on the promoters of pro-apoptotic genes, such as Bax and PIG-3.3 Similarly, p53β preferentially enhances p53 transcriptional activity on the Bax but not p21 promoter.4 In addition, hCAS/ CSE1L, a factor identified in the p53 transcription complex, specifically associ-ates with the PIG-3 promoter to induc