8-methyl G (8meG)

FULL NAME: 8-methylguanine

8-Methyl-2'-deoxyguanosine (8-medGuo) has been shown to be a major stable alkylation product of 2'-deoxyguanosine induced by methyl radical attack on DNA. Recent studies have suggested that carbon-centered radicals can be a source of C8-alkylated lesions. 8-Methylguanine (8MeG) was shown to be produced in vitro in RNA and DNA by methyl radicals generated by oxidation of 1,2-dimethylhydrazine and methylhydrazine, respectively. Other studies have shown that 8meG can also be produced in vitro and in vivo by genotoxic agents such as tert-butylhydroperoxide, diazoquinones and arenediazonium ions. These findings are significant as they suggest a possible contribution of 8MeG in the carcinogenic effects of these agents, especially 1,2-dimethylhydrazine, which induces adenocarcinomas of the colon in rodents. Site-specific studies using 8MedG-containing oligonucleotides prepared by phosphoramidite synthesis have explored the mutagenicity and toxicity of this lesion. It was found that 8MeG on the template strand blocks in vitro extension of DNA by mammalian polymerase α, but not by the E.coli Klenow fragment. The products from the primer extension reaction were then analyzed for mutations. 8MeG was found to direct exo− Klenow fragment-based incorporation of dCMP most of the time (77%) but also paired occasionally with deoxyguanosine monophosphate (dGMP) (1.1%) and dAMP (0.41%). Similar numbers were obtained for extension assays with mammalian polymerase α. Replication with the Klenow fragment also introduced small amounts of one (0.38%) and two (0.81%) base-pair deletions . These numbers mirror the thermodynamic stability of the 8MeG:deoxynucleoside monophosphate base (dNMP) pair, decreasing in the order dCMP > dGMP > dAMP >> dTMP. 1,2-Dimethylhydrazine induces both O6MeG and 8MeG in similar amounts in the DNA of rats. However, the mutation frequencies of 8MeG are two orders of magnitude less than those of O6MeG. Therefore, we may conclude that 8MeG is a weakly mutagenic lesion that in principle can contribute to G → C transversions in cells. The repair of 8MeG has been studied. Only AlkA was able to excise 8MeG. Human MPG did not repair 8MeG, nor did any of the glycosylases involved in repair of oxidative damage (Fpg, Nth of E.coli; Ntg1, Ntg2, Ogg1 of Saccharomyces cerevisiae and human Ogg1). 8MeG has been shown to stabilize the Z-conformation of DNA in short oligonucleotides even in low salt concentrations. This property may be relevant in vivo as Z-DNA is thought to have a role in the regulation of DNA supercoiling. This lesion is also used as a chemical modification to stabilize quadruplex structures of G-rich sequences of DNA, which are proposed to have a role in telomeric DNA stability and in repression of transcription at the c-myc promoter. The wide range of potential biological activities of this lesion makes it a prime target for future investigations.

DAMAGE TYPE: methylation damage

methyl radicals

no mutagenesis
stalled replication fork

G→A transition
G→C transversion
point mutation

base excision repair (BER)

DNA repair protein(s) related to damage:

Last modification date: Oct. 15, 2011