Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint.
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.
Vries
Robert G J
RG
Department of Molecular and Cell Biology, Leiden University Medical Centre, 2300 RA Leiden, The Netherlands.
Bezrookove
Vladimir
V
Zuijderduijn
Lobke M P
LM
Kia
Sima Kheradmand
SK
Houweling
Ada
A
Oruetxebarria
Igor
I
Raap
Anton K
AK
Verrijzer
C Peter
CP
D019943:Amino Acid Substitution / Q000235:genetics; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008938:Mitosis / Q000235:genetics*; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D011123:Polyploidy; D018335:Rhabdoid Tumor / Q000235:genetics*; D000071796:SMARCB1 Protein; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors