3-methyl A (3meA)

FULL NAME: 3-methyladenine

N3-methyladenine (3MeA) can be formed in DNA by methylating agents as well as non-enzymatically by intracellular SAM. In a mammalian cell, SAM or some other methylating agent reacts with DNA to generate an estimated 600 3MeA per day. The half-life of 3MeA in vivo is estimated to be between 4–24 h. While 3MeA is not particularly mutagenic, it is a cytotoxic DNA lesion by virtue of its ability to block replication or by virtue of its ability to give rise to a chemically or enzymatically generated abasic/apurinic site (AP site). With regard to replication inhibition, it is thought that the methyl at the N3 position of purines sterically interferes with the required contact between the polymerase and minor groove on DNA. This property makes it essential for the cell to have in place defenses against this form of damage. 3MeA-DNA-glycosylases have evolved in both prokaryotic and eukaryotic systems to afford the efficient repair of this lesion. The prokaryotic system includes the highly selective and constitutive 3-methyladenine-DNA glycosylase I (TAG) protein and the inducible AlkA glycosylase with a broader specificity. The eukaryotic system is comprised of human 3MeA-DNA-glycosylase (AAG) and N-methylpurine-DNA glycosylase (MPG). AlkA and TAG repair 3MeA with equal efficiency on double-stranded DNA, but AlkA is 10- to 20-fold more efficient on single-stranded DNA. There is also evidence that UvrA, an ATPase and DNA-binding protein of the NER pathway, may be able to mitigate the cytotoxic effects of this lesion. The cytotoxicity of 3MeA is well established in the literature. In vitro studies showing chain termination one nucleotide 3′ to adenines in methylated DNA templates pointed to 3MeA as a strong block to DNA replication. 3MeA in DNA has also been shown to be toxic in E.coli. 3MeA can also cause p53 induction, S phase arrest, sister chromatid exchange, chromosome aberrations and apoptosis in mammalian cells. As with N7-methylguanine (7MeG), enhanced repair of 3MeA by DNA-glycosylases of the BER pathway can lead to a flood of AP sites that can also contribute to mutations and lethality. 3-Methyladenine is commonly used as a specific inhibitor of autophagic sequestration. It blocks autophagy by inhibition of PI3K activity, an enzyme required for autophagy. 3MeA is not considered to be a seriously promutagenic lesion based upon work done in bacterial and in yeast systems. In 3MeA-DNA-glycosylase I (tag)-deficient E.coli mutants, treatment with MNU leads to a 5-fold increase in mutation frequency only under SOS-induced conditions. Furthermore, in repair-proficient cells, removal of 3MeA from the DNA does not show a significant difference in mutagenesis in SOS-induced versus SOS-uninduced cells.

DAMAGE TYPE: methylation damage

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)
SN1 methylating agents
SN2 methylating agents
N-methyl-N-nitrosourea (NMU)
methyl methanesulfonate (MMS)
alkylating agents


A→T transversion
cell cycle arrest
point mutation
stalled replication fork

A→T transversion
point mutation

base excision repair (BER)

DNA repair protein(s) related to damage:

Last modification date: Nov. 15, 2011