Reduced Potassium Dependency 3 Small (Rpd3S) histone deacetylase complex (Rpd3S)

The Reduced Potassium Dependency 3 Small (Rpd3S) histone deacetylase complex is a critical epigenetic regulator responsible for maintaining transcriptional fidelity and chromatin stability. In yeast, it consists of the catalytic subunit Rpd3 along with Sin3, Ume1, Rco1, and Eaf3, while its human orthologs are primarily represented by the Sin3-HDAC1/2 complexes. Rpd3S is unique for its recruitment to the coding regions of actively transcribed genes, where it recognizes the H3K36me3 epigenetic mark to deacetylate histones in the wake of RNA polymerase II, thereby suppressing the initiation of deleterious cryptic transcription. In human pathology, the catalytic components of the Rpd3S-like complex—HDAC1 and HDAC2—are frequently overexpressed in various cancers, contributing to tumor progression by silencing regulatory genes and promoting cell survival. This has made the complex a major therapeutic target for histone deacetylase inhibitors (HDACis) such as Vorinostat and Romidepsin, which are FDA-approved for certain lymphomas. Beyond oncology, the complex is also investigated for its roles in neurodegeneration and inflammatory diseases, as its regulation of the epigenetic landscape influences broad cellular responses to stress and DNA damage.

Other names

RPD3C(S)Rpd3-Sin3 small complexSin3-HDAC complexHistone deacetylase Rpd3Sin3B complex (human ortholog)Rpd3S complex

Inhibition of the catalytic activity of class I histone deacetylases (HDAC1, HDAC2, and HDAC3), leading to increased global and site-specific histone acetylation, which promotes the re-expression of tumor suppressor genes and disrupts the transcription of genes necessary for cell survival.