O6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the O6-methylguanine DNA methyltransferase (MGMT) gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.
Although alkylatingmutagens preferentially modify the guanine base at the N7 position, O6-alkyl-guanine is a major carcinogenic lesion in DNA. This DNA adduct is removed by the repair protein O6-alkylguanine DNA alkyltransferase through a SN2 reaction mechanism. This protein is not a true enzyme since it removes the alkyl group from the lesion in a stoichiometric reaction and the active enzyme is not regenerated after it is alkylated (referred to as suicide enzyme). The methyl-acceptor residue in the protein is a cysteine.
Methylation of the gene's promoter may play a significant role in carcinogenesis. In patients with glioblastoma multiforme, a severe type of brain tumor, the methylation state of the MGMT gene determined whether tumor cells would be responsive to temozolomide; if the promoter was methylated, temozolomide was more effective. On a clinical level, this translates into a prolonged survival of glioblastoma patients with a methylated MGMT promoter. In addition, MGMT methylation can be used to predict patient survival in clinical prediction models. For testing of the MGMT promoter methylation status in the clinical setting, DNA-based methods such as methylation-specific polymerase chain reaction (MS-PCR) or pyrosequencing are preferred over immunohistochemical or RNA- based essays.
MGMT has also been shown to be a useful tool increasing gene therapy efficiency. By using a two component vector consisting of a transgene of interest and MGMT, in vivo drug selection can be utilized to select for successfully transduced cells.
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