How do regulatory switches achieve high sensitivity within the noisy cellular milieu? Loewer et AG-1478 al. and Prives 2009 Exquisitely sensitive to DNA damage p53 can respond to even one or two breaks in nuclear DNA but it apparently ignores harmless breaks that naturally form as DNA is opened during the replication phase of the cell cycle. Thus a central question has been how p53 maintains its high level of sensitivity to mutagenic harm while simultaneously looking over harmless breaks during regular cell AG-1478 department. With this presssing problem of or cell-cycle arrest. On the other hand bursts of p53 activated by extrinsic mutagens such as for example radiation and medicines perform activate and halt cell department. Incredibly the duration and intensity of the p53 pulses were similar below both conditions. How then will p53 differentiate between harmless breaks in DNA and possibly dangerous types? Loewer and co-workers find how the critical signal managing the AG-1478 experience of p53 can be an complex balance of substitute posttranslational adjustments of p53. Latest studies have discovered that like histone proteins p53 may be the focus on of myriad posttranslational adjustments at several lysine (K) residues mainly at its carboxyl terminus area (Shape 1) (Vousden and Prives 2009 Kruse and Gu 2009). Much like many histone protein acetylation activates p53 whereas methylation can either activate (at K372) or repress (at K370 K373 and K382) this transcription element (Huang and Berger 2008 Huang et al. 2010 Oddly enough a number of these substitute adjustments occur on a single or adjacent lysine residues in the carboxyl terminus (Shape 1). Furthermore these lysines could be ubiquitinated to focus on p53 for degradation also. Shape 1 Posttranslational Adjustments Regulate p53 Activity The importance and need for these lysine adjustments in p53’s carboxyl terminus have already been controversial. Several research with transgenic mice discovered that mutating a subset of the lysines had just RAB21 modest results on the experience of p53 (Toledo and Wahl 2006 On the other hand a subsequent research in cell tradition discovered that p53 function was significantly decreased when all acetylated sites had been mutated (Tang et al. 2008 Nevertheless research with mice built expressing this acetylation-deficient type of p53 never have been reported however. Increasing the complexity from the tale lysine methylation which happens at lots of the same residues as acetylation (Shape 1) seems to repress p53 activity (Vousden and Prives 2009 Huang and Berger 2008 That is confusing as the framework of repression is not clear; will methylation maintain low basal activity of p53 through the regular cell routine or can it attenuate the experience of p53 after a tension response? One potential description for the conflicting outcomes of the practical studies is these lysines could be on the other hand acetylated for activation methylated for repression and ubiquitinated for degradation. Therefore the opposing actions of the adjustments might face mask the consequences of eliminating the lysine residues from p53. Quite simply substitution from the lysines with additional residues leads towards the simultaneous lack of activating and repressing adjustments and thus feasible shared suppression in vivo. The single-cell strategy utilized by Loewer and colleagues supports this latter hypothesis. They find that only cells experiencing true DNA mutagenesis possess acetylated p53 (i.e. the activated form of p53) and induce the transcription of during the normal cell AG-1478 cycle. These results indicate that repressive methylations on p53 keep it in check as it pulses during cell division; when actual DNA damage occurs acetylation replaces the methylation to trigger p53 transcriptional activity. Although this new study provides an elegant framework for understanding how the balance between methylation and acetylation of p53 may regulate its activity many questions emerge from these results. For example does methylation of lysine residues in the DNA binding domain of p53 (at K120 and AG-1478 K164; Figure 1) also block acetylation and activation of p53 (Vousden and Prives 2009 In addition there is evidence that deacetylases and demethylases also regulate p53 (Kruse and Gu 2009; Huang et al. 2007 and it is important to understand how these different classes of enzymes target p53 especially in terms of their role in cancer and tumorigenesis. Further it will be interesting to learn how ubiquitination at these same residues is integrated into the scheme that regulates p53. One reasonable overall.