Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice.
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.
Wellcome Trust Centre for Cell Biology, The King's Buildings, Edinburgh University, Edinburgh EH9 3JR, UK.
Catherine B
CB
Millar
Jacky
J
Guy
Owen J
OJ
Sansom
Jim
J
Selfridge
Eilidh
E
MacDougall
Brian
B
Hendrich
Peter D
PD
Keightley
Stefan M
SM
Bishop
Alan R
AR
Clarke
Adrian
A
Bird
D044503:5-Methylcytosine; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D020137:Base Pair Mismatch; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D003641:Deamination; D015226:Dinucleoside Phosphates / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D007414:Intestinal Neoplasms / Q000209:etiology / Q000235:genetics*; D007420:Intestine, Large; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017354:Point Mutation; D013489:Suppression, Genetic
D044503:5-Methylcytosine; D003596:Cytosine; D015226:Dinucleoside Phosphates; D004706:Endodeoxyribonucleases; C015772:CpG dinucleotide; C492249:Mbd4 protein, mouse