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The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimicks class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention. Author summary: Histone deacetylases (HDACs) remove acetyl groups from histones and non-histone proteins. Dysregulated acetylation has been attributed to various disease states, including cancer, immunological and neurological diseases. Due to the potential reversibility of epigenetic or post-translational modifications, the pharmacological targeting of HDACs has high potential. However, most HDAC inhibitors used for clinical trials lack specificity which might contribute to side effects. Despite many years of intense research, surprisingly little is known about the substrate specificity of individual HDAC enzymes. To elucidate the consequences of more specific targeting of individual HDAC isoforms, detailed analysis of the catalytic function of each enzyme is required. Albeit HDACs being well studied in general, cross-comparison between the studies is difficult due to the use of different model systems and the frequent use of inhibitors, which lack specificity. Also, commonly used knockout or knockdown models abolish the structural function of the enzymes, potentially not accurately reflecting the situation of inhibitor treatment which only causes enzymatic inactivation. We suggest that the use of catalytic inactive mutants instead of knockouts might be another step towards mimicking isoform specific enzyme inhibition and provide a detailed comparative, side-by-side analysis of class I HDACs. [ABSTRACT FROM AUTHOR]