Identification of Mammalian Sds3 as an Integral Component of the Sin3/Histone Deacetylase Corepressor Complex

Abstract

Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease.

Leila Alland and Gregory David contributed equally to this work.

We thank Thomas Graf, Nicole Schreiber-Agus, and Nabeel Bardeesy for helpful discussions, Maria Dudas and Carlos Cordon-Cardo for providing mouse embryo sections, and Annick Harel-Bellan for advice on histone deacetylase assays. We also thank Jim DeCaprio and Richard Maser for critical reading of the manuscript.

This work was supported by NIH grant K11CA68266 (L.A. and R.A.D.), the Ruth Estrin Goldberg Memorial Award (L.A.), an American Cancer Society Young Investigator Award (L.A.), and Human Frontier Science Program Organization (G.D.). R.A.D. is an American Cancer Society Research Professor.