Characterizing the Sin3A/HDAC1 complex: an alternative strategy for the precise inhibition of deacetylase activity in cells

Histone acetylation is a key epigenetic mechanism controlling chromatin structure and DNA accessibility. The levels of acetylation are controlled by the opposing activities of histone acetyl transferases (HAT) and histone deacetylase (HDAC) enzymes. Approximately 50% of the total HDAC activity in cells is contributed by HDAC1 and HDAC2 (HDAC1/2), highly homologous proteins found in one of four multi-protein complexes (Sin3, NuRD, CoREST and MiDAC). Incorporation into these complexes is crucial for HDAC1/2 function as they activate enzymatic activity and determine substrate specificity. Inhibition of HDAC1/2, using knock-outs and knock-down, has indicated important roles in cell cycle progression, DNA damage repair, DNA synthesis and the regulation of gene expression. HDAC inhibitors have shown positive effects in a number of diseases states (cancer, epilepsy, neurodegenerative disease, HIV infection, etc.). Sin3 contains four unique and highly conserved PAH domains, a four helical bundle, which bind specifically to transcription factors and chromatin associated proteins. We hypothesize, that by establishing a role for individual PAH domains within Sin3A/B complex activities will provide a much more precise way to regulate HDAC activity in cells than the non-selective inhibitors currently used in the clinic.