cytidylyl-3--5--guanosine and Intestinal-Neoplasms

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.

Topics: 5-Methylcytosine; Alleles; Amino Acid Sequence; Animals; Base Pair Mismatch; Cytosine; Deamination; Dinucleoside Phosphates; DNA Methylation; DNA Repair; Endodeoxyribonucleases; Female; Gene Targeting; Genes, APC; Genetic Predisposition to Disease; Intestinal Neoplasms; Intestine, Large; Loss of Heterozygosity; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Point Mutation; Suppression, Genetic