Rb targets histone H3 methylation and HP1 to promoters

Abstract

In eukaryotic cells the histone methylase SUV39H1 and the methyl-lysine binding protein HP1 functionally interact to repress transcription at heterochromatic sites. Lysine 9 of histone H3 is methylated by SUV39H1 (ref. 2), creating a binding site for the chromo domain of HP1 (refs 3, 4). Here we show that SUV39H1 and HP1 are both involved in the repressive functions of the retinoblastoma (Rb) protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E promoter, and in fibroblasts that are disrupted for SUV39, the activity of the cyclin E and cyclin A2 genes are specifically elevated. Chromatin immunoprecipitations show that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. These results indicate that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other co-repressor proteins.

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…The well-known tumour-suppressor gene, RB1, which was deleted in the RET/PTC-positive group of tumours and which is a key gene in the FAS signalling pathway (Nagata, 1994) is linked to the caspase cascade in the apoptosis pathway by CASP3 (Riedl and Salvesen, 2007). In normal cells an activation of RB1 by CASP3 leads to a repressed transcription of a series of cell cycle proteins by recruiting methyl-transferases that subsequently induce transcription-inactive heterochromatin (Tan and Wang, 1998;Nielsen et al, 2001). A lack of this process RB1-deleted tumour cells may lead to increased genomic instability and tumour progression.…”

Retinoblastoma family genes

“…Endogenous Rb associates with SUV39H1, an enzyme which methylates lysine 9 on histone H3. Additionally, HP1, a protein which binds methylated lysine 9 and is associated with transcriptionally silent regions of chromatin, can bind Rb (Nielsen et al, 2001). Furthermore, Rb interacts with the DNA methyltransferase enzyme DNMT1, which cooperates to repress reporter genes (Robertson et al, 2000); however, DNA methylation was not detected at the repressed promoters, suggesting that the effect of DNMT1 may not be through its enzymatic activity but instead might help recruit other co-repressors.…”

Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer

“…Independent evidence has shown physical interaction of several members of the pRb/p130-E2F4/F5-HDAC1-SUV39H1 complex, for example, pRb and E2F, pRb and HDAC, and pRb and SUV39H1. 10,11 How does SUV39H1 fit into the complex and, most importantly, what event triggers the replacement of histone acetyltransferase p300 with DNMT1? Finally, one should not overlook the fact that the ERa gene is a large genetic unit that spans approximately 300 kb at 6q25.1, including the 140 kb containing the eight protein coding exons.…”