Abstract
Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases
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Cadherins / metabolism
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Catalytic Domain
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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DNA Helicases / genetics*
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DNA Helicases / metabolism*
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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HeLa Cells
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Humans
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
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Molecular Sequence Data
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Mutation
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism*
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription, Genetic
Substances
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Cadherins
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Cell Cycle Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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R-cadherin
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Repressor Proteins
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Alcohol Oxidoreductases
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lactate-malate transhydrogenase
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Protein-Tyrosine Kinases
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WEE1 protein, human
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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DNA Helicases
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CHD5 protein, human
Grants and funding
This work was supported by the Dana-Farber Cancer Institute, the William F. Milton Fund, and the Claudia Adams Barr Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.