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J. Biol. Chem., Vol. 279, Issue 50, 52353-52360, December 10, 2004

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Activation-induced Cytidine Deaminase Deaminates 5-Methylcytosine in DNA and Is Expressed in Pluripotent Tissues

IMPLICATIONS FOR EPIGENETIC REPROGRAMMING^*

Hugh D. Morgan, Wendy Dean, Heather A. Coker¶, Wolf Reik**, and Svend K. Petersen-Mahrt¶||

From the Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom, the ^¶DNA Editing Laboratory, Cancer Research UK, Clare Hall Laboratories, South Mimms EN6 3LD, United Kingdom, and the ^||Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. The Aid and Apobec1 genes are located in a cluster of pluripotency genes including Nanog and Stella and are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.

Received for publication, July 8, 2004 , and in revised form, September 7, 2004.

^* This work was supported by the Medical Research Council, Biotechnology and Biological Sciences Research Council, and Cancer Research United Kingdom. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Funded in part by a C. J. Martin Postdoctoral Fellowship.

Supported in part by the Arthritis Research Campaign.

^** To whom correspondence should be addressed. E-mail: wolf.reik{at}bbsrc.ac.uk.

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