Repair of O6-MeG by MGMT
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
Repair of O6-MeG by MGMT

Alkylating reagents cause damage to DNA (mainly at O6-G (Guanine), O4-T (Thymine) and O2-T positions in DNA) similar to that induced by ultraviolet irradiation. The bases altered by these reagents are primarily purines (phosphate oxygen is also targets), and the spectrum of products formed varies with the reagent used. An unusual form of DNA repair involving active reversal of DNA damage is present in mammalian cells to correct such miscoding alkylation lesion (Ref.1). The most highly mutagenic of these products is O6-MeG (O6-Methylguanine), which has a very high probability of pairing with thymine when the modified strand replicates. O6-MeG is generated endogenously in small amounts by reactive cellular catabolites.

Two major pathways exist in mammalian cells for the removal and repair of alkylation and oxidative DNA damage (Ref.3). The most direct mechanism for repairing alkylation DNA damage involves the DNA repair protein MGMT (O6-Methylguanine-DNA Methyltransferase or AGT), which removes alkyl groups from DNA. MGMT repairs the damage by transferring a methyl or ethyl group from an O6-MeG (O6-Methylguanine) or O6-Ethylguanine residue to a cysteine residue in the active site of the protein. It does this by accepting the methyl or ethyl group itself. Thus, MGMT (like photo reactivation) directly changes damaged bases rather than removing them. Because this reaction results in irreversible inactivation of the protein molecule, MGMT is commonly described as a ‘suicide enzyme’. If left unrepaired, O6-MeG adducts can mispair with thymine, causing a G: C A: T transition that is associated with both mutagenesis and carcinogenesis (Ref.2).

DNA damage caused by oxygen alkylation of bases has been correlated with the mutagenic and carcinogenic potency of monofunctional alkylating agents. O6-MeG pairs ambiguously with both C and T, causing transition mutations. The methylated nucleoside is probably flipped out from DNA to be accommodated in an active-site pocket of the repair enzyme. This epigenetically controlled damage reversal function is occasionally not expressed, leading to cytotoxic abortive attempts to correct the lesion by mismatch repair. In bacteria O6-alkylguanine alkyltransferase regulates both its own transcription and that of another repair enzyme, a DNA-N-glycosylase.