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.Chromatin-remodeling complexes modulate nucleosome structure in an ATP-dependent manner (40, 49). The 2-MDa multisubunit SWI/SNF complex was the first such complex identified in yeast and is highly conserved among eukaryotes (14, 54). Mammalian SWI/SNF complexes are heterogenous but have several common subunits, including SNF5 (Ini1), BAF155/BAF170, and one of the highly homologous ATPase subunits (Brm or Brg1) (46,72). SWI/SNF complexes play important roles in transcriptional regulation (both activation and repression) and contribute to the control of diverse cellular processes, such as proliferation and differentiation (21,39,44,59,63). Gene-targeting experiments with mice have shown that the mammalian SWI/SNF complex is essential for early embryonic development, since homozygous inactivation of genes encoding different subunits (Brg1, Snf5, or Swi3/Srg3) results in peri-implantation lethality (11,22,37,38,57).Accumulating genetic evidence has defined SNF5/Ini1 as a tumor suppressor gene in humans and mice. Homozygous inactivating mutations or deletions in the SNF5 gene in humans are associated with malignant rhabdoid and atypical teratoid/ rhabdoid tumors (7, 62, 69). These are rare, but very aggressive, pediatric tumors that arise primarily in the brain and kidney. Furthermore, we and others have shown that Snf5 functions as a tumor suppressor gene in mice. Heterozygous Snf5 ϩ/Ϫ animals develop tumors at a high incidence via loss of heterozygosity (LOH) at the Snf5 locus. These tumors share histological features with their human counterparts and develop at very specific sites, mainly in the nervous system (22, 38, 57). Recently, it was shown that mice with a reversible conditional mutation of Snf5 developed early, and fully penetrant, T-cell lymphomas (58). Several studies have also revealed that Brg1 is mutated or deleted in a variety of human tumor cell lines (74). Mice heterozygous for a Brg1-null mutation are cancer prone and develop tumors of epithelial origin without loss of heterozygosity (11).It is still unclear whether the tumor suppressor function of Snf5 depends on SWI/SNF act...