The mammalian DNA (cytosine-5) methyltransferase (Dnmt1) is involved in the maintenance of methylation patterns in the genome during DNA replication and development. The retinoblastoma gene product, Rb, is a cell cycle regulator protein that represses transcription by recruiting histone deacetylase (HDAC1). In vivo, histone deacetylase associates with Dnmt1. Here we show that Rb itself associates with human Dnmt1 (hDnmt1) independently of its own phosphorylation status. Methyltransferase activity was co-purified with Rb. The regulatory domain of hDnmt1 binds strongly to the B and C pockets of Rb (amino acids 701-872) and inhibits methyltransferase activity by disruption of the hDnmt1-DNA binary complex. Weak interaction of Rb pockets A and B with Dnmt1 was also observed. Overexpression of Rb leads to hypomethylation of the cellular DNA, suggesting that Rb may modulate Dnmt1 activity during DNA replication in the cell cycle.
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