Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex

The gene encoding the SNF5/Ini1 core subunit of the SWI/SNF chromatin remodeling complex is a tumor suppressor in humans and mice, with an essential role in early embryonic development. To investigate further the function of this gene, we have generated a Cre/lox-conditional mouse line. We demonstrate that Snf5 deletion in primary fibroblasts impairs cell proliferation and survival without the expected derepression of most retinoblastoma protein-controlled, E2F-responsive genes. Furthermore, Snf5-deficient cells are hypersensitive to genotoxic stress, display increased aberrant mitotic features, and accumulate phosphorylated p53, leading to elevated expression of a specific subset of p53 target genes, suggesting a role for Snf5 in the DNA damage response. p53 inactivation does not rescue the proliferation defect caused by Snf5 deficiency but reduces apoptosis and strongly accelerates tumor formation in Snf5-heterozygous mice.     

Global role for chromatin remodeling enzymes in mitotic gene expression

Regulation of eukaryotic gene expression requires ATP-dependent chromatin remodeling enzymes, such as SWI/SNF, and histone acetyltransferases, such as Gcn5p. Here we show that SWI/SNF remodeling controls recruitment of Gcn5p HAT activity to many genes in late mitosis and that these chromatin remodeling enzymes play a role in regulating mitotic exit. In contrast, interphase expression of GAL1, HIS3, PHO5, and PHO8 is accompanied by SWI/SNF-independent recruitment of Gcn5p HAT activity. Surprisingly, prearresting cells in late mitosis imposes a requirement for SWI/SNF in recruiting Gcn5p HAT activity to the GAL1 promoter, and GAL1 expression also becomes dependent on both chromatin remodeling enzymes. We propose that SWI/SNF and Gcn5p are globally required for mitotic gene expression due to the condensed state of mitotic chromatin.     

Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer

The SWI/SNF complex is a chromatin-remodeling complex that uses the energy of ATP hydrolysis to modify chromatin structure in order to regulate gene expression. The SWI/SNF complex is evolutionarily conserved in all eukaryotes and is comprised of a catalytic subunit, either of BRG1 (also known as SMARCA4) or of BRM (also known as SMARCA2), and a variety of associated proteins that can modulate the recruitment of the complex and its activity. Key observations link the SWI/SNF complex with cancer. First, two of its subunits (SNF5 and BRG1) bear cancer-inactivating mutations and thus are bona fide tumor suppressors. The SNF5 gene is biallelically inactivated in malignant rhabdoid tumors (MRTs) whereas BRG1 is mutated in cancer cell lines of several types, such as those of the breast, prostate, lung, pancreas and colon. Second, mice heterozygous for mutations at Snf5 and Brg1 are cancer-prone, and, third, BRG1 binds or is related to important tumor-suppressor proteins. The present review focuses on the biological function and genetics of BRG1, particularly with respect to its role as a tumor suppressor.