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.
Department of Animal and Cell Biology, The Institute for Life Sciences, The Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel. agnesk@md.huji.ac.il
Agnes
A
Klochendler-Yeivin
Eli
E
Picarsky
Moshe
M
Yaniv
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry* / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D050684:E2F Transcription Factors / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D006128:Growth; D051379:Mice; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D018335:Rhabdoid Tumor / Q000473:pathology; D016196:S Phase / Q000235:genetics; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000737:chemistry* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D000071796:SMARCB1 Protein; C445179:SWI-SNF-B chromatin-remodeling complex; C513265:Smarcb1 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53