title: Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress.
abstract: 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.
authors.affiliation: Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Brandl
authors.forename: Tobias
authors.initials: T
authors.lastname: Wagner
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Uhlig
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Knauer
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stauber
authors.forename: Frauke
authors.initials: F
authors.lastname: Melchior
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011499:Protein Processing, Post-Translational; D058207:Sumoylation; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2