Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint

Genes Dev. 2005 Mar 15;19(6):665-70. doi: 10.1101/gad.335805.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Cell Line
  • Chromatin Assembly and Disassembly / genetics*
  • Chromosomal Instability / genetics*
  • Chromosomal Proteins, Non-Histone
  • Cytogenetic Analysis
  • DNA-Binding Proteins / genetics*
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genes, Tumor Suppressor
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mitosis / genetics*
  • Mutagenesis
  • Mutation / genetics*
  • Polyploidy
  • Rhabdoid Tumor / genetics*
  • SMARCB1 Protein
  • Signal Transduction / genetics
  • Transcription Factors

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors