Histone deacetylase 2 (HDAC2) is relevant for homeostasis and plays a critical role in gastrointestinal cancers. Here, we report that post-translational modification of endogenous HDAC2 with small ubiquitin-related modifier 1 (SUMO1) is a new regulatory switch for the tumor suppressor p53. Sumoylation of HDAC2 at lysine 462 allows binding of HDAC2 to p53. Moreover, sumoylated HDAC2 is a previously not recognized biologically relevant site-specific deacetylase for p53. Deacetylation of p53 at lysine 320 by sumoylated HDAC2 blocks recruitment of p53 into promoter-associated complexes and p53-dependent expression of genes for cell cycle control and apoptosis. Thereby, catalytically active sumoylated HDAC2 restricts p53 functions and attenuates DNA damage-induced apoptosis. Genotoxic stress evokes desumoylation of HDAC2, enabling p53-dependent gene expression. Our data show a new molecular mechanism involving a dynamically controlled HDAC2-sumoylation/p53-acetylation switch that regulates cell fate decisions following genotoxic stress.
