Dimethyl Sulfate (DMS(

This is a mutagen that is a monofunctional alkylating agent of structure CH₃–O–SO₂–O–CH₃, which reacts with nucleophilic sites primarily by an S_N2 mechanism. This mechanism involves a concerted process with the substrate, resulting in selective methylation of only the most nucleophilic sites. Thus DMS predominantly methylates nitrogen atoms on nucleic acids, only rarely oxygen or phosphorus. By far the most abundant lesion produced is N7-methylguanine, with minor amounts of N₁-, N₃-, and N₇-methyladenine and N₃-methyl cytosine, and trace amounts of O₆-methylguanine (1). 7-Methylguanine has base-pairing properties very similar to guanine itself, so this modification is probably not the most important cause of mutagenesis by DMS. Both 3-methyladenine and 3-methylcytosine can cause base mispairing, which may lead directly to mutagenesis by DMS (1, 2). Although probably not primarily involved in mutagenesis, methylation at the N7 of guanine significantly weakens the N9-glycosidic bond, leading to enhanced formation of apurinic sites (3-5). Depurination may also occur at 3-methylated adenines (6, 7), and this itself has mutagenic consequences.

 DMS is both carcinogenic and mutagenic in a wide variety of organisms, producing point mutations, chromosomal aberrations, and recombinational events (reviewed by Hoffman (8)). In many mutagenesis studies, DMS is reported to be a base-pair substitution mutagen, but it also causes frameshift mutations and deletions. It has been suggested that much of the data can be explained in terms of effects of DMS on DNA repair processes (8, 9). Lawley and Warren (2) found that Escherichia coli repair processes effectively remove 3-methylguanine and 3-methyladenine, but not 7-methylguanine, residues from DNA. These authors suggested that N-3 purine alkylations may block DNA replication and stimulate enzymatic repair processes. Inaccuracies in these may lead to many of the observed mutations in bacterial systems. 7-Methylguanine is removed from the DNA of mammalian cells, although it does not interfere with DNA synthesis (10).

References

1. P. D. Lawley, D. J. Orr, and S. A. Shah (1972) Chem. Biol. Interact. 5, 286–288. 

2. P. D. Lawley and W. Warren (1976) Chem. Biol. Interact. 12, 211–220. 

3. P. D. Lawley (1966) Prog. Nucleic Acid. Res. Mol. Biol. 5, 89–131. 

4.P. D. Lawley (1974a) In Molecular and Environmental Aspects of Mutagenesis (L. Prakash, ed.), Thomas, Springfield, IL, pp. 17–33. 

5. P. D. Lawley (1974b) Mutat. Res. 23, 283–295. 

6. P. D. Lawley and P. Brookes (1963) Biochem. J. 89, 127–138. 

7. R. H. C. San and H . F. Stich (1975) Int. J. Cancer 16, 284–291. 

8. G. R. Hoffman (1980) Mutat. Res. 75, 63–129. 

9. J. W. Drake and R. H. Baltz (1976) Annu. Rev. Biochem. 45, 11–37. 

10. D. A. Scicchitano and P. C. Hanawalt (1990) Mutat. Res. 233, 31–38.