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Science 19 July 2002:
Vol. 297. no. 5580, pp. 403 - 405
DOI: 10.1126/science.1073354
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Reports

Enhanced CpG Mutability and Tumorigenesis in MBD4-Deficient Mice

Catherine B. Millar,1* Jacky Guy,1* Owen J. Sansom,2* Jim Selfridge,1 Eilidh MacDougall,1 Brian Hendrich,1 Peter D. Keightley,3 Stefan M. Bishop,2 Alan R. Clarke,2 Adrian Bird1dagger

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 rightarrow  T transitions at CpG sites was increased by a factor of three. On a cancer-susceptible ApcMin/+ background, Mbd4-/- mice showed accelerated tumor formation with CpG rightarrow  TpG mutations in the Apc gene. Thus MBD4 suppresses CpG mutability and tumorigenesis in vivo.

1 Wellcome Trust Centre for Cell Biology, The King's Buildings, Edinburgh University, Edinburgh EH9 3JR, UK.
2 Cardiff School of Biosciences, Cardiff University, Post Office Box 911, Cardiff CF10 3US, UK.
3 Institute of Cell Animal and Population Biology, The King's Buildings, Edinburgh University, Edinburgh EH9 3JT, UK.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: a.bird{at}ed.ac.uk

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