DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters

Methylation of CpG islands is associated with transcriptional silencing and the formation of nuclease-resistant chromatin structures enriched in hypoa cetylated histones(1-3). Methyl-CpG-binding proteins, such as MeCP2, provid e a link between methylated DNA and hypoacetylated histones by recruiting h istone deacetylase(4,5), but the mechanisms establishing the methylation pa tterns themselves are unknown. Whether DNA methylation is always causal for the assembly of repressive chromatin or whether features of transcriptiona lly silent chromatin might target methyltransferase remains unresolved. Mam malian DNA methyltransferases show little sequence specificity in vitro, ye t methylation can be targeted in vivo within chromosomes to repetitive elem ents(6,7), centromeress(8-10) and imprinted loci(11). This targeting is fre quently disrupted in tumour cells, resulting in the improper silencing of t umour-suppressor genes associated with CpG islands(1,2). Here we show that the predominant mammalian DNA methyltransferase, DNMT1, co-purifies with th e retinoblastoma (Rb) tumour suppressor gene product, E2F1. and HDAC1 and t hat DNMT1 cooperates with Rb to repress transcription from promoters contai ning E2F-binding sites. These results establish a link between DNA methylat ion, histone deacetylase and sequence-specific DNA binding activity, as wel l as a growth-regulatory pathway that is disrupted in nearly all cancer cel ls.