Increased DNA Damage Sensitivity and Apoptosis in Cells Lacking the Snf5/Ini1 Subunit of the SWI/SNF Chromatin Remodeling Complex

Abstract

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.

We are grateful to Moshe Oren for helpful discussions and Jonathan Weitzman for critical reading of the manuscript. We thank Aharon Razin, Ruthy Shemer, and the friends from the Department of Cell Biochemistry and Human Genetics (Hadassah Medical School, Hebrew University) for their help and contribution to this work.

This work was supported by the Israel Cancer Research Fund (ICRF project grant) and Association for International Cancer Research grants 00-221 and 03-109 (A.K.-Y.).