Abstract
The DNA repair protein, O(6)-methylguanine DNA-methyltransferase (MGMT) prevents mutations and cell death that result from aberrant alkylation of DNA. The polymorphic variants Leu84Phe, Ile143Val, and Lys178Arg are frequent in the human population. We review here studies of these and other MGMT polymorphisms and their association with risk for lung, breast, colorectal and endometrial cancer with a consideration of gene-environment interactions. In addition, we review studies of the effects of polymorphic variation on alkyltransferase activity and expression. It is formally possible that polymorphic variation could modify functions of MGMT other than its alkyltransferase activity. While it was previously reported that an alkylated form of MGMT modifies Estrogen Receptor alpha activity, from our studies we conclude that this regulation is not a major function of MGMT. Overall, the effects of polymorphic variation on protein function are subtle, and further investigation is required to provide a comprehensive mechanism that explains the observed associations of these variants with risk for cancer.
Publication types
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Research Support, N.I.H., Extramural
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Review
MeSH terms
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Amino Acid Substitution
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Base Sequence
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DNA Modification Methylases / chemistry
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DNA Modification Methylases / genetics*
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DNA Modification Methylases / metabolism*
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DNA Primers / genetics
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DNA Repair
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DNA Repair Enzymes / chemistry
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DNA Repair Enzymes / genetics*
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DNA Repair Enzymes / metabolism*
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DNA, Complementary / genetics
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Estrogen Receptor alpha / metabolism
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Female
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Genetic Variation
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Humans
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In Vitro Techniques
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Male
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Models, Molecular
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Neoplasms / etiology
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Neoplasms / genetics
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Neoplasms / metabolism
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O(6)-Methylguanine-DNA Methyltransferase / chemistry
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O(6)-Methylguanine-DNA Methyltransferase / genetics*
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O(6)-Methylguanine-DNA Methyltransferase / metabolism*
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Polymorphism, Single Nucleotide
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism*
Substances
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DNA Primers
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DNA, Complementary
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Estrogen Receptor alpha
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Recombinant Proteins
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Tumor Suppressor Proteins
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DNA Modification Methylases
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MGMT protein, human
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O(6)-Methylguanine-DNA Methyltransferase
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DNA Repair Enzymes