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Nucleic Acids Research, 1994, Vol. 22, No. 6 972-976
© 1994

CHEMISTRY

The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA

Jiang-Cheng Shen, William M. Rideout, III and Peter A. Jones*

Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, School of Medicine Los Angeles, CA 90033, USA

* To whom correspondence should be addressed

Received December 23, 1993. Revised February 9, 1994. Accepted February 9, 1994.

The modified base, 5-methylcytosine, constitutes approximately 1 % of human DNA, but sites containing 5-methylcytoslne account for at least 30% of all germline and somatic point mutations. A genetic assay with a sensitivity of 1 in 107, based on reversion to neomycln resistance of a mutant pSV2-neo plasmid, was utilized to determine and compare the deamination rates of 5-methylcytosine and cytosine in double-stranded DNA for the first time. The rate constants for spontaneous hydrolytic deamination of 5-methylcytosine and cytosine in double-stranded DNA at 37°C were 5.8x10–13 s–1 and 2.6x10–13 S–1, respectively. These rates are more than sufficient to explain the observed frequency of mutation at sites containing 5-methylcytoslne and emphasize the Importance of hydrolytic deamination as a major source of human mutations.


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