| Health / Medical Topics |
hSWI-SNF Pathway
The eukaryotic genome is packaged by histone and nonhistone proteins to form chromatin. The assembly of nucleosomes, as well as compaction of nucleosomal arrays into higher-order chromatin structures, creates a highly restrictive environment for nuclear processes that require access to DNA. The packaging of eukaryotic DNA into nucleosomes inhibits the access of factors to DNA and thus results in the repression of transcription, replication, and recombination. To counterbalance the repressive nature of chromatin, a variety of chromatin remodeling factors use the energy of ATP hydrolysis to facilitate the interaction of proteins with nucleosomal DNA. ATP dependent chromatin remodeling complexes are characterized by the presence of an ATPase subunit from the SNF2-like family of the DEAD/H (SF2) DNA-stimulated ATPases. The highly conservative hSWI/SNF multisubunit complexes contain hBRM or BRG1 ATPases which alter the histone-DNA contacts enabling the access of general transcription factors to promoter regions. Remodeling complexes are targeted to promoters via interactions with sequence-specific transcription factors. Since chromatin constitutes a barrier for processes affecting DNA, such a transcription, replication, and repair, a mechanism is required that can open up or remodel chromatin to make it accessible to replication and transcription factors. Steroid receptors are a class of transcription factors that can interact with the repressive chromatin structure and remodel the chromatin to allow other transcription factors to bind. In addition to nuclear receptors, transcription activators as divergent as erythroid Kruppel-like factor, C/EBPs, c-Myc, MyoD, HSF1, and EBNA2 have also been found to recruit SWI/SNF to specific promoters. The role of steroid receptors in chromatin remodeling and transcription is exemplified by the glucocorticoid receptor (GR)-mediated transactivation of the mouse mammary tumor virus (MMTV) promoter. The MMTV promoter is organized into a phased array of six nucleosomes when stably integrated into mammalian cells. The second nucleosome (nucB) is positioned over the binding sites for the GR and nuclear factor 1 (NF1). Binding of NF1 is essential for GR-mediated transactivation of the MMTV promoter; in the absence of glucocorticoid, the chromatin structure of the promoter excludes the binding of NF1. Upon hormone administration, GR recruits an ATP-dependent remodeling hSWI/SNF complex (BRG1-BAF) to remodel the chromatin Individually, the GR makes direct interactions with BRG1-associated factor 60a (BAF60a) and BAF57. Further, BAF60a possesses at least two interaction surfaces, one for GR and BRG1 and a second for BAF155 and BAF170.The remodeling process converts the closed conformation of the MMTV promoter to an open one without altering the nucleosomal positioning. The remodeling of the promoter permits NF1 binding and the assembly of a transcription initiation complex. (NCI Thesaurus/BIOCARTA)
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