RETINOBLASTOMA PROTEIN RECRUITS HISTONE DEACETYLASE TO REPRESS TRANSCRIPTION

The retinoblastoma protein (Rb) silences specific genes that are activ e in the S phase of the cell cycle and which are regulated by E2F tran scription factors(1). Rb binds to the activation domain of E2F and the n actively represses the promoter by a mechanism that is poorly unders tood(2,3). Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb 'pocket' domain. Association with the deacetyla se is reduced by naturally occurring mutations in the pocket and by bi nding of the human papilloma virus oncoprotein E7. We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cy cle protein cyclin E. Inhibition of histone deacetylase activity by tr ichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter. Our results indicate that histone d eacetylases are important for regulating the cell cycle and that activ e transcriptional repression by Rb may involve the modification of chr omatin structure.