O-6-methylguanine-DNA methyltransferase

O-6-methylguanine-DNA methyltransferase
	; PDB rendering based on 1eh6.
Available structures
PDB	1EH6, 1EH7, 1EH8, 1QNT, 1T38, 1T39, 1YFH
Identifiers
Symbols	MGMT;
External IDs	OMIM: 156569 MGI: 96977 HomoloGene: 31089 GeneCards: MGMT Gene
EC number	2.1.1.63
Gene Ontology
Molecular function	• DNA binding; • methylated-DNA-[protein-cysteine S-methyltransferase activity]; • calcium ion binding; • methyltransferase activity; • DNA-methyltransferase activity; • transferase activity;
Cellular component	• nucleus; • nucleoplasm;
Biological process	• DNA ligation; • DNA repair; • DNA methylation; • DNA dealkylation involved in DNA repair; • response to toxin; • methylation; • cellular response to oxidative stress; • response to drug; • regulation of caspase activity; • response to ethanol; • positive regulation of DNA repair; • response to folic acid; • negative regulation of cell death; • mammary gland epithelial cell differentiation; • cellular response to organic cyclic compound; • cellular response to ionizing radiation;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs

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Methylated-DNA-protein-cysteine methyltransferase is an enzyme that in humans is encoded by the MGMT gene.^[1]^[2]

[edit] Function

O(6)-alkyl-guanine is the major carcinogenic lesion in DNA induced by alkylating mutagens. This DNA adduct is removed by the repair protein, O(6)-methylguanine-DNA methyltransferase. This protein is not a true enzyme since it accepts the alkyl group from the lesion in a stoichiometric reaction and the active enzyme is not regenerated after it is alkylated. The methyl-acceptor residue in the protein is cysteine.^[3]

[edit] Clinical significance

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.^[4]

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 utalized to select for successfully transduced cells.^[5]

[edit] Interactions

O-6-methylguanine-DNA methyltransferase has been shown to interact with estrogen receptor alpha.^[6]

[edit] See also

[edit] References

^ Tano K, Shiota S, Collier J, Foote RS, Mitra S (January 1990). "Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O6-alkylguanine". Proc. Natl. Acad. Sci. U.S.A. 87 (2): 686–90. doi:10.1073/pnas.87.2.686. PMC 53330. PMID 2405387. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=53330.
^ Natarajan AT, Vermeulen S, Darroudi F, Valentine MB, Brent TP, Mitra S, Tano K (January 1992). "Chromosomal localization of human O6-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization". Mutagenesis 7 (1): 83–5. doi:10.1093/mutage/7.1.83. PMID 1635460.
^ Kaina B, Christmann M, Naumann S, Roos WP (August 2007). "MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents". DNA Repair (Amst.) 6 (8): 1079–99. doi:10.1016/j.dnarep.2007.03.008. PMID 17485253.
^ Hegi ME, Diserens AC, Gorlia T, et al. (2005). "MGMT gene silencing and benefit from temozolomide in glioblastoma". N. Engl. J. Med. 352 (10): 997–1003. doi:10.1056/NEJMoa043331. PMID 15758010.
^ Chang AH, Stephan MT, Lisowski L, et al. (2008). "Erythroid-specific Human Factor IX Delivery From In Vivo Selected Hematopoietic Stem Cells Following Nonmyeloablative Conditioning in Hemophilia B Mice". Molecular Therapy 16 (10): 1745–1752. doi:10.1038/mt.2008.161. PMC 2658893. PMID 18682698. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2658893.
^ Teo AK, Oh HK, Ali RB, Li BF (October 2001). "The Modified Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase Is a Negative Regulator of Estrogen Receptor-Mediated Transcription upon Alkylation DNA Damage". Mol. Cell. Biol. 21 (20): 7105–14. doi:10.1128/MCB.21.20.7105-7114.2001. PMC 99886. PMID 11564893. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=99886.

[edit] Further reading

Margison GP, Povey AC, Kaina B, Santibáñez Koref MF (2003). "Variability and regulation of O6-alkylguanine-DNA alkyltransferase". Carcinogenesis 24 (4): 625–35. doi:10.1093/carcin/bgg005. PMID 12727789.