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RESEARCH COMMUNICATION
1 Department of Molecular and Cell Biology, Leiden University Medical Centre, 2300 RA Leiden, The Netherlands; 2 Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, 3015 GE Rotterdam, The Netherlands
The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Here, we report that loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbated poly- and aneuploidization, due to abrogated chromosome segregation. We found that hSNF5 activates the mitotic checkpoint through the p16INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that poly- and aneuploidy of tumor cells can result from mutations in a chromatin remodeler.
[Keywords: Chromosomal instability; chromatin; tumor suppressor; hSNF5/INI1/Baf47/SmarcB1]
Received January 12, 2005; revised version accepted January 27, 2005.
3 These authors contributed equally to this work.
4 Present address: Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
5 Corresponding author.
E-MAIL c.verrijzer{at}erasmusmc.nl; FAX 31-10-40879472.
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