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Rb-mediated chromatin structure regulation and transcriptional repression

Oncogene volume 20, pages 3134–3138 (2001)Cite this article

The retinoblastoma protein, Rb, is encoded by a classic tumor suppressor gene that is mutated in a large variety of tumors. Extensive studies have suggested that Rb functions as a tumor suppressor by blocking cell cycle progression, although it has also been implicated in the regulation of differentiation and development. It is now thought that Rb inhibits cell proliferation mainly by negatively regulating the transcription of certain genes that are required for cell cycle progression. Rb lacks a DNA binding domain and is tethered to promoters through its interaction with other sequence-specific transcription factors, such as members of the E2F family proteins. Rb binds the transcription activation domain of E2F and blocks its activity. More importantly, the Rb-E2F complex also actively represses transcription (i.e. inhibiting the activity of neighboring enhancer elements) on promoters that contain E2F sites. Assembly of such Rb-E2F repressor complexes on promoters is critical for Rb-mediated growth suppression. Here, we review studies that address the mechanism of transcriptional repression by Rb, particularly in the context of chromatin structure regulation.

The formation of nucleosomes from chromosomal DNA and histone octomers, together with the further packaging of nucleosomes into chromatin, prevent the access of transcription factors to promoters and are often associated with genes that are transcriptionally inactive. Nucleosome formation is regulated by post-translational modification of the amino terminals of histones, which are exposed in the nucleosomal structure. The best studied of these modifications is acetylation/deacetylation (Hassig and Schreiber, 1997). Acetylation neutralizes the positive charge on lysine residues in the histone tails, therefore leads to the disruption of nucleosome structure and ‘unwrapping’ of chromosomal DNA which allows access of transcription factors. The enzymes responsible for the acetylation of histones, histone acetyltransferases (HATs), are associated with a number of transcription activators, and are thought to act as co-activators by disrupting nucleosome structure and thereby facilitating transcription machinery gain access to the promoter (Grunstein, 1997). On the other hand, histone deacetylases (HDACs), which currently have eight family members, remove acetyl groups from histone tails and promote nucleosome formation. HDACs have been shown to associate with an increasing number of transcriptional repressors (Pazin and Kadonaga, 1997).

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  1. Division of Molecular Oncology, Washington University School of Medicine, St. Louis, 63110, Missouri, MO, USA

    H Steven Zhang & Douglas C Dean

  2. Sangamo BioSciences Inc., Richmond, 94804, California, CA, USA

    H Steven Zhang

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Zhang, H., Dean, D. Rb-mediated chromatin structure regulation and transcriptional repression. Oncogene 20, 3134–3138 (2001). https://doi.org/10.1038/sj.onc.1204338

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