O-6-methylguanine-DNA methyltransferase

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O-6-methylguanine-DNA methyltransferase
PBB Protein MGMT image.jpg
PDB rendering based on 1eh6.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol MGMT
External IDs OMIM156569 MGI96977 HomoloGene31089 GeneCards: MGMT Gene
EC number 2.1.1.63
RNA expression pattern
PBB GE MGMT 204880 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4255 17314
Ensembl ENSG00000170430 ENSMUSG00000054612
UniProt P16455 P26187
RefSeq (mRNA) NM_002412 NM_008598
RefSeq (protein) NP_002403 NP_032624
Location (UCSC) Chr 10:
131.27 – 131.57 Mb
Chr 7:
136.89 – 137.13 Mb
PubMed search [1] [2]

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.[1][2] 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.[3] The two bacterial isozymes are Ada and Ogt.

Function and mechanism[edit]

'O6-alkylguanine DNA alkyltransferase'
Identifiers
EC number 2.1.1.63
CAS number 77271-19-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Although alkylating mutagens 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.[4]

structural formula of 6-O-Methylguanosine\mathrm{\ \xrightarrow{MGMT} }structural formula of Guanosine

Demethylation of 6-O-Methylguanosine to Guanosine

Clinical significance[edit]

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.[5] 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.[6] 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.[7]


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.[8]

Interactions[edit]

O6-methylguanine-DNA methyltransferase has been shown to interact with estrogen receptor alpha.[9]

See also[edit]

References[edit]

  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. 
  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. ^ Shiraishi A, Sakumi K, Sekiguchi M (October 2000). "Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase". Carcinogenesis 21 (10): 1879–1883. doi:10.1093/carcin/21.10.1879. PMID 11023546. 
  4. ^ 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): 1079–1099. doi:10.1016/j.dnarep.2007.03.008. PMID 17485253. 
  5. ^ 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. 
  6. ^ Molenaar, Remco J. (2014). "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-Oncology. doi:10.1093/neuonc/nou005. PMID 24510240. 
  7. ^ M. Preusser, Charles R. Janzer, J. Felsberg, G. Reifenberger, M. F. Hamou, A. C. Diserens, R. Stupp, T. Gorlia, C. Marosi, H. Heinzl, J. A. Hainfellner, M. Hegi: Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. In: Brain Pathol. 2008 Oct;18(4), S. 520–532. doi:10.1111/j.1750-3639.2008.00153.x. Epub 2008 Apr 8.
  8. ^ 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. 
  9. ^ 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. 

Further reading[edit]

  • 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.