O-6-methylguanine-DNA methyltransferase

O-6-methylguanine-DNA methyltransferase

PDB rendering based on 1eh6.
Identifiers
Symbols MGMT;
External IDs OMIM: 156569 MGI: 96977 HomoloGene: 31089 GeneCards: MGMT Gene
EC number 2.1.1.63
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]

Contents

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

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. 
Transferase: one carbon transferases (EC 2.1)
2.1.1: Methyl-
N-
O-
Other
2.1.2: Hydroxymethyl-,
Formyl- and Related
Other
2.1.3: Carboxy- and Carbamoyl
Carboxy
Carbamoyl
2.1.4: Amidino
B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6