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Nucleic Acids Research, 1995, Vol. 23, No. 8 1380-1387
© 1995

MOLECULAR BIOLOGY

Hhal and Hpall DNA methyltransferases bind DNA mismatches, methylate uracil and block DNA repair

Allen S. Yang, Jiang-Cheng Shen, Jean-Marc Zingg, Sha Mi1 and Peter A. Jones*

Department of Biochemistry and Molecular Biology, Urological Cancer Research Laboratory, Kenneth Norris Jr Comprehensive Cancer Center, University of Southern California School of Medicine Los Angeles, CA 90033, USA 1Spring Harbor Laboratory, Cold Spring Harbor NY 11724, USA

* To whom correspondence should be addressed

Received December 15, 1994. Revised February 28, 1995. Accepted February 28, 1995.

The hydrolytic deamination of 5-methyicytosine (5-mC) to thymine (T) is believed to be responsible for the high mutability of the CpG dinucleotide in DNA. We have shown a possible alternate mechanism for mutagenesis at CpG in which Hpall DNA-(cytosine-5) methyltransferase (M.Hpall) can enzymatically deaminate cytosine (C) to uracil (U) in DNA [Shen,J.-C., Rideout,W.M., III and Jones,P.A., Cell, 71, 1073–1080, (1992)]. Both the hydrolytic deamination of 5-mC and enzymatic deamination of C create premutagenic DNA mismatches (G:U and G:T) with the guanine (G) originally paired to the normal C. Surprisingly, we found that DNA-(cytosine-5) methyltransferases have higher affinities for these DNA mismatches than for their normal G:C targets and are capable of transfer ring a methyl group to the 5-position of U, creating T at low efficiencies. This binding by methyltransferase to mismatches at the recognition site prevented repair of G:U mismatches by uracil DNA glycosyiase in vitro.


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