The retinoblastoma protein (pRB) is a tumor suppressor protein that can act as a transcriptional repressor, but the mechanisms underlying this function are unclear and controversial. In the July 17 Proceedings of the National Academy of Sciences, Kennedy et al., from the Massachusetts General Hospital Cancer Center, describe the use of a yeast model system to address the mechanism of pRB repression (Proc Natl Acad Sci USA 2001, 98:8720-8725). They expressed a chimeric protein in which the large pocket domain of mammalian pRB was fused to the DNA binding (DB) domain of the yeast Gal4p factor. The DB-pRB protein could repress expression of a HIS3 reporter gene under the control of a promoter containing Gal4p binding sites. A tumor-derived pRB mutant lacking exon 22 failed to repress HIS3 expression. However, another mutant pRB protein that is defective in binding to LXCXE-containing proteins retained transcriptional repression in yeast. Experiments in mutant yeast strains showed that pRB repression required an intact RPD3 histone deacetylase gene and the RbAp48 ortholog MSI1, but not SIN3 or SAP30 activities. The authors propose that, MSI1 mediates recruitment of histone deacetylases to the pRB protein for trascriptional repression.