The p53-HAT connection

Multiple structural, biochemical and in vivo studies have solidified the role that histone acetyltransferases (HATs) play in regulation of the p53 pathway. 1 HATs are known to modulate p53 functions in many ways, from regulating its stability to promoting acetyla-tion-dependent interactions with DnA as well as various co-factors and chromatin modi-fiers. 1 Of these, p300, CBP, PCAF and Tip60 are the most well-studied p53 co-factors that can regulate (sometimes selectively) a number of bona fide p53 targets involved in cell cycle, apoptosis, DnA repair, metabolism and other processes. 2 Of particular current interest is the time-and stress-dependent interplay between different acetyltransferases. yet, though we now know the players, we still have only limited knowledge of their performances. A paper by Love et al. in a previous issue of Cell Cycle, has contributed new insight into the function of one such HAT. 3 Using multiple p53-activating stress conditions in combination with siRnA-mediated knockdown of specific HATs in several cancer cell lines, the authors have demonstrated the dependence of p21-driven cell cycle arrest on the his-tone acetyl transferase activity of PCAF. They found that PCAF, but not p300 or CBP (two closely related and well characterized tran-scriptional co-activators) is absolutely required for maximal p21 expression in several settings. intriguingly, their work indicates that PCAF is exclusively important for the activation of cell cycle arrest through p53-but not Rb-dependent pathways. A pictorial description of possible events leading to p21 activation is shown in Figure 1. Key features of the paper by Love et al. are summarized as follows. First, PCAF-dependent effects on p21 transcription are apparently unrelated to its reported MDM2-directed e3 ligase activity, which otherwise would result in subsequent elevation of p53 levels.