title: BRG1 mutations found in human cancer cell lines inactivate Rb-mediated cell-cycle arrest.
abstract: Eukaryotic organisms package DNA into chromatin for compact storage in the cell nucleus. However, this process promotes transcriptional repression of genes. To overcome the transcriptional repression, chromatin remodeling complexes have evolved that alter the configuration of chromatin packaging of DNA into nucleosomes by histones. The SWI/SNF chromatin remodeling complex uses energy from ATP hydrolysis to reposition nucleosomes and make DNA accessible to transcription factors. Recent studies showing mutations of BRG1, one of two mutually exclusive ATPase subunits, in human tumor cell lines and primary tissue samples have implicated a role for its loss in cancer development. While most of the mutations lead to complete loss of BRG1 protein expression, others result in single amino acid substitutions. To better understand the role of these BRG1 point mutations in cancer development, we characterized SWI/SNF function in human tumor cell lines with these mutations in the absence of BRM expression, the other ATPase component. We found that the mutant BRG1 proteins still interacted with the core complex members and appeared at the promoters of target genes. However, while these mutations did not affect CD44 and CDH1 expression, known targets of the SWI/SNF complex, they did abrogate Rb-mediated cell-cycle arrest. Therefore, our results implicate that these mutations disrupt the de novo chromatin remodeling activity of the complex without affecting the status of existing nucleosome positioning.
authors.affiliation: Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bartlett
authors.forename: Tess J
authors.initials: TJ
authors.lastname: Orvis
authors.forename: Gary S
authors.initials: GS
authors.lastname: Rosson
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Weissman
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002868:Chromosomal Proteins, Non-Histone; D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; D004265:DNA Helicases