MGMT

Official Full Name

O-6-methylguanine-DNA methyltransferase

Organism

Homo sapiens

GeneID

4255

Background

Alkylating agents are potent carcinogens that can result in cell death, mutation and cancer. The protein encoded by this gene is a DNA repair protein that is involved in cellular defense against mutagenesis and toxicity from alkylating agents. The protein catalyzes transfer of methyl groups from O(6)-alkylguanine and other methylated moieties of the DNA to its own molecule, which repairs the toxic lesions. Methylation of the genes promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma. [provided by RefSeq, Sep 2015]

Synonyms

MGMT; O-6-methylguanine-DNA methyltransferase; methylated-DNA--protein-cysteine methyltransferase; methylguanine-DNA methyltransferase; O-6-methylguanine-DNA-alkyltransferase; O6-methylguanine-DNA methyltransferase; 6-O-methylguanine-DNA methyltransferase;

Bio Chemical Class

Methyltransferase

Protein Sequence

MDKDCEMKRTTLDSPLGKLELSGCEQGLHEIKLLGKGTSAADAVEVPAPAAVLGGPEPLMQCTAWLNAYFHQPEAIEEFPVPALHHPVFQQESFTRQVLWKLLKVVKFGEVISYQQLAALAGNPKAARAVGGAMRGNPVPILIPCHRVVCSSGAVGNYSGGLAVKEWLLAHEGHRLGKPGLGGSSGLAGAWLKGAGATSGSPPAGRN

Open

Disease

Sarcoma

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

O6-methylguanine-DNA-methyltransferase (MGMT) is a ubiquitous DNA repair enzyme and is closely related to the occurrence and development of various tumors. The MGMT gene is expressed in the nucleus of the human body with the ability to divide and proliferate. The normal and cancerous stomach and colon are close to the nucleus of the luminal epithelial cells, and MGMT is expressed in the basal cell nucleus of normal tissues and cancer tissues of patients with lung cancer, melanoma and ovarian cancer.

The study found that the expression of MGMT was different in normal cells and cancer cells of different tissues. The expression of MGM T gene was the strongest in normal tissues, the expression of bone marrow cells was weak, and the expression of nerve cells was the weakest. MGMT gene expression in tumor cells from high to low is breast cancer, gastric cancer, small cell lung cancer, non-small cell lung cancer, kidney cancer, brain tumor, esophageal cancer, colon cancer, malignant melanoma. The expression of MGMT was also different in different races. The study found that the expression rate of MGMT in European hepatocellular carcinoma (HCC) was about 62.0%, while the expression rate of MGMT in Asian hepatocellular carcinoma was only 39.1%. According to the activity of MGM T, tumor cells are divided into two types, including Mer + type cells and Mer - type cells. Mer+ cells have high MGM T activity, can effectively repair DNA alkylation damage, and are resistant to alkylating agents. Mer-type cells have low MGMT activity and cannot effectively repair DNA alkylation damage and are sensitive to alkylating agents.

Figure 1. Summary of different known modulators of MGMT gene expression. (Cabrini, G. , et al. 2015)

The Mechanism of Action of MGMT

MGMT contains a group of proteins that regulate nucleosomes and histone acetylase (CBP/p300) complex, which activates nuclear receptor transcriptional activity by integrating external signals to prepare for DNA transcription. The complex removes the O 6-guanine adduct from the DNA and transfers the alkyl group of 6-RG (O 6-methylgunine O 6-methyl-deoxyguanine) to its own cysteine On the acid residue, avoid the G:C→A:T gene mutation caused by methylation, protecting normal tissues from alkylating agent damage and does not involve other proteins or cofactors before DNA damage occurs. When the MGMT active site is bound by an alkyl group, it is converted to inactivated R-MGMTa, and R-MGMTa acts as an endogenous estrogen receptor (ER) regulator, which blocks the proliferation of ER-driven cells, even when Its ligand estradiol (E2) can also exert a barrier effect in the presence of it.

MGMT and Cancer

The expression of MGMT gene methylation was more prominent in advanced lung cancer tissues, but not in early lung cancer tissues. In the gene sequencing of 62 patients with non-small cell lung cancer, it was found that the methylation status of MGMT gene was not correlated with age, gender, pathological type and differentiation status, and was related to tumor stage. The methylation rate of MGMT gene was significantly higher in patients with advanced lung cancer than in the early stage (the methylation rate of III and IV was 33.3%, which was significantly higher than 0% in stage I and II). Studies have shown that 31 cases of proximal colon cancer, 43 cases of distal colon cancer found that MGMT methylation in the distal colon cancer is significantly higher than the proximal colon cancer. The study also found that the ability of DNA repair is closely related to the polymorphism of the MGMT gene and causes different individuals to have different susceptibility to tumors.

References:

Cabrini, G. , Fabbri, E. , Lo Nigro, C. , Dechecchi, M. , & Gambari, R. . (2015). Regulation of expression of o6-methylguanine-dna methyltransferase and the treatment of glioblastoma (review). International Journal of Oncology.
Juyeon Lee., Ki-Jong Rhee., Sung-Hoon Kim., & Yoon Suk Kim.. (2015). O6-methylguanine-dna methyltransferase (mgmt) gene expression is associated with ultraviolet b (uvb)-induced cell growth inhibition and recovery. Genes & Genomics, 37(9), 789-796.
Leblanc, V. G. , & Marra, M. A. . (2016). Dna methylation in adult diffuse gliomas. Briefings in Functional Genomics, elw019.

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