The protein p53 exerts a pivotal role in controlling the cell cycle, apoptosis and DNA repair in response to various forms of genotoxic stress. The rapid activation of p53 following genotoxic stress is ensured through complex regulation that occurs mainly at the post-translational level. Huang and colleagues now add an extra factor to the regulation of p53 by showing that the lysine methyltransferase SMYD2 methylates p53.

The authors first showed that SMYD2 monomethylates p53 at residue K370 in vitro and in vivo. But what is the significance of this modification for p53 function? SMYD2 negatively regulates the expression of p53-responsive genes (such as p21 and Mdm2 ) in a p53-dependent manner, and it does so by downregulating the transcriptional activity of p53. Increased amounts of SMYD2 resulted in reduced p53 binding to the p21 promoter, and decreased levels of promoter-associated p53 correlated with decreasing amounts of p21 mRNA and protein. This indicated that SMYD2-mediated K370 modification reduces the DNA-binding efficiency of p53.

Huang and co-workers also investigated a possible crosstalk between the previously identified SET9-mediated p53-activating K372 modification and the p53-repressing K370 modification. Intriguingly, K372 methylation inhibits K370 methylation in vitro and in vivo. On the basis of these data, the authors proposed that “there is an equilibrium between promoter-bound and free p53.” SMYD2-mediated K370 methylation results in the dissociation of p53 from DNA, whereas SET9-mediated K372 methylation promotes the association of p53 with promoters by blocking SMYD2-mediated methylation.

What does all of this have to do with the p53 response to genotoxic stresses? The authors propose that this mechanism could provide a rapid response to DNA damage. In physiological conditions, SMYD2-mediated methylation of K370 holds p53 in an inactive state. However, following DNA damage the SET9-mediated K372 modification inhibits SMYD2-mediated methylation and promotes binding of p53 to promoters of genes that control cell-cycle arrest and apoptosis. Whether SMYD2 might function as an oncoprotein that methylates p53 and represses its tumour-suppressive function remains to be seen.