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  • Review Article
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MGMT: its role in cancer aetiology and cancer therapeutics

Nature Reviews Cancer volume 4, pages 296–307 (2004)Cite this article

Key Points

  • The DNA-repair protein O6-alkylguanine-DNA-alkyltransferase (AGT) is encoded by the gene O6-methylguanine-DNA-methyltransferase (MGMT).

  • AGT removes alkylating lesions at position O6 of guanine and therefore has an important role in maintaining normal cell physiology and genomic stability.

  • A broad range of expression of AGT is noted across tumours and normal tissues. Its expression also helps to prevent carcinogenesis and is a target for chemotherapy.

  • Overexpression of MGMT reduces the risk of carcinogenesis and the risk of mutations after exposure to methylating agents.

  • Loss of MGMT is associated with increased carcinogenic risk and increased sensitivity to methylating agents.

  • MGMT-promoter methylation shuts off MGMT expression in tumours and increases responsiveness to chemotherapy.

  • O6-benzylguanine is a specific inhibitor of AGT, but mutations in the active-site pocket of the protein can cause resistance to the drug.

  • MGMT genes with such mutations are effective for use in gene therapy for transducing drug resistance into haematopoietic stem cells, to protect these cells from the toxic effects of chemotherapy.

  • The physiological role of MGMT remains an area of active investigation.

Abstract

The DNA-repair protein O6-alkylguanine DNA alkyltransferase (AGT) has a wide range of activity in normal tissues and its evolutionary conservation indicates a fundamental role in cell physiology and maintenance of the genome. Through removal of alkylating lesions at O6 of guanine, AGT protects against mutagenesis and malignant transformation. In tumours, AGT provides resistance to treatment with alkylating agents, unless expression is lost by methylation of the promoter of the gene encoding AGT — O6-methylguanine-DNA-methyltransferase (MGMT) — or there is direct inhibition of AGT activity. When overexpressed in stem cells, MGMT serves as a drug-selection gene for gene therapy and protects normal tissues from the toxic effects of chemotherapy.

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Figure 1: AGT repair process.
Figure 2: MGMT overexpression prevents MNU-induced T-cell lymphomas.
Figure 3: Crystal structure/model of O6-BG bound to AGT.
Figure 4: Hypersensitivity of Mgmt-knockout mice to nitrosoureas.
Figure 5: Deletion of AGT and pharmacokinetics of O6-BG after O6-BG infusion.
Figure 6: Mutant MGMT stem-cell selection.

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Acknowledgements

This work was supported by grants from the National Institutes of Health. The author thanks J. Reese, J. Roth and K. Lingus for figure preparation and for reviewing the manuscript.

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  1. Case Comprehensive Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, 10900 Euclid Ave, Cleveland, 44106, Ohio, USA

    Stanton L. Gerson

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DATABASES

Cancer.gov

breast cancer

colon cancer

gastrointestinal carcinoid tumours

gliomas

Hodgkin's lymphoma

lung cancer

melanoma

myeloma

non-Hodgkin's lymphoma

pancreatic cancer

retinoblastomas

LocusLink

CDKN1A

CDKN2A

KRAS

LMO1

MGMT

Mlh1

MSH2

MSH6

p53

Glossary

NUCLEOTIDE EXCISION REPAIR

(NER). A DNA-repair complex consisting of recognition, removal and synthetic proteins that repair bulky adducts in a transcription-coupled manner.

BASE EXCISION REPAIR

(BER). A DNA-repair pathway for single-base abnormalities consisting of a glycosylase, apurinic endonuclease, β-polymerase and other scaffolding and synthesis proteins.

MISMATCH REPAIR

A DNA repair complex that detects and repairs incorrectly paired nucleotides that are introduced during DNA replication.

SN1 DONOR

A substitution nucleophile reaction in which the rate-determining step occurs with only one molecule.

CpG ISLANDS

Short runs in DNA of cytosine–guanine repeats; when methylated at 5′C in promoter regions, gene silencing results.

HISTONE DEACETYLASE INHIBITOR

These inhibitors alter the acetylation pattern on key nuclear-DNA-bound histones, altering the chromatin pattern of nucleosomes and altering transcription-factor binding. In general, histone deacetylase inhibitors result in open chromatin configuration, increasing gene expression.

IC50

A measure of the concentration of drug that is needed to inhibit 50% of the enzyme.

GLIADEL WAFER

Wafers containing bis-(2-chloroethyl)-nitrosourea that are implanted into the tumour site at the time of surgery and slowly release the drug over 2–3 weeks.

RIBOZYMES

RNA molecules with catalytic activity. They can be engineered to cleave specific mRNAs, thereby blocking gene expression at the mRNA level.

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Gerson, S. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4, 296–307 (2004). https://doi.org/10.1038/nrc1319

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