Abstract
The mammalian protein MBD4 contains a methyl-CpG binding domain and can enzymatically remove thymine (T) or uracil (U) from a mismatched CpG site in vitro. These properties suggest that MBD4 might function in vivo to minimize the mutability of 5-methylcytosine by removing its deamination product from DNA. We tested this hypothesis by analyzing Mbd4-/- mice and found that the frequency of of C --> T transitions at CpG sites was increased by a factor of three. On a cancer-susceptible Apc(Min/+) background, Mbd4-/- mice showed accelerated tumor formation with CpG --> TpG mutations in the Apc gene. Thus MBD4 suppresses CpG mutability and tumorigenesis in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Methylcytosine
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Alleles
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Amino Acid Sequence
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Animals
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Base Pair Mismatch
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Cytosine / analogs & derivatives*
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Cytosine / metabolism
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DNA Methylation
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DNA Repair
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Deamination
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Dinucleoside Phosphates / genetics*
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Endodeoxyribonucleases / genetics*
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Endodeoxyribonucleases / physiology*
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Female
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Gene Targeting
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Genes, APC
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Genetic Predisposition to Disease
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Intestinal Neoplasms / etiology
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Intestinal Neoplasms / genetics*
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Intestine, Large
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Loss of Heterozygosity
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Male
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Point Mutation*
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Suppression, Genetic
Substances
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Dinucleoside Phosphates
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cytidylyl-3'-5'-guanosine
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5-Methylcytosine
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Cytosine
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Endodeoxyribonucleases
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Mbd4 protein, mouse