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.
Millar
Catherine B
CB
Wellcome Trust Centre for Cell Biology, The King's Buildings, Edinburgh University, Edinburgh EH9 3JR, UK.
Guy
Jacky
J
Sansom
Owen J
OJ
Selfridge
Jim
J
MacDougall
Eilidh
E
Hendrich
Brian
B
Keightley
Peter D
PD
Bishop
Stefan M
SM
Clarke
Alan R
AR
Bird
Adrian
A
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