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
Species	Human	Mouse
Entrez	4255	17314
Ensembl	ENSG00000170430	ENSMUSG00000054612
UniProt	P16455	Q4VA39
RefSeq (mRNA)	NM_002412.3	NM_008598.2
RefSeq (protein)	NP_002403.2	NP_032624.1
Location (UCSC)	Chr 10: 131.27 – 131.57 Mb	Chr 7: 144.09 – 144.32 Mb
PubMed search	[1]	[2]

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

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]

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 promotor 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]

Interactions

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

See also

• 6-O-Methylguanine
• DNA methyltransferase
• Methyltransferase

References

1. ^ 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. 
2. ^ 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. 
3. ^ 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. 
4. ^ 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. 
5. ^ 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. 
6. ^ 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. 

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.