Methylated-DNA-protein-cysteine methyltransferase

Last updated
MGMT
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MGMT , Mgmt, AGT, AI267024, Agat, O-6-methylguanine-DNA methyltransferase
External IDs OMIM: 156569; MGI: 96977; HomoloGene: 31089; GeneCards: MGMT; OMA:MGMT - orthologs
EC number 2.1.1.63
Orthologs
SpeciesHumanMouse
Entrez

4255

17314

Ensembl

ENSG00000170430

ENSMUSG00000054612

UniProt

P16455

P26187

RefSeq (mRNA)

NM_002412

NM_008598
NM_001377037

RefSeq (protein)

NP_002403

NP_032624
NP_001363966

Location (UCSC) Chr 10: 129.47 – 129.77 Mb Chr 7: 136.5 – 136.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Methylated-DNA--protein-cysteine methyltransferase(MGMT), also known as O6-alkylguanine DNA alkyltransferaseAGT, is a protein that in humans is encoded by the MGMT gene. [5] [6] MGMT 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. [7] The two bacterial isozymes are Ada and Ogt.

Contents

Function and mechanism

'O6-alkylguanine DNA alkyltransferase'
Identifiers
EC no. 2.1.1.63
CAS no. 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
Search
PMC articles
PubMed articles
NCBI proteins

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 an SN2 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 a suicide enzyme). The methyl-acceptor residue in the protein is a cysteine. [8]

6'-O-Methylguanosine.svg Guanosin.svg

Demethylation of 6-O-methylguanosine to Guanosine

Clinical significance

In patients with glioblastoma, a severe type of brain tumor, the cancer medicine temozolomide is more effective in those with a methylation of the gene's promoter. [9] Overall, MGMT methylation is associated with prolonged patient survival in clinical prediction models. [10] 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 assays. [11]

In patients with pituitary tumours, MGMT can predict the clinical and radiological response to treatment with temozolomide. In this context the MGMT status is optimally assessed by immunohistochemistry, with MGMT depleted tumours expected to demonstrate a response. [12] Promotor methylation status (of MGMT) does not predict temozolomide response because, in pituitary tumours, the promotor is almost always unmethylated. [13]

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. [14]

Mutagens in the environment, [15] in tobacco smoke, [16] food, [17] as well as endogenous metabolic products [18] generate reactive electrophilic species that alkylate or specifically methylate DNA, generating 6-O-methylguanine (m6G).

In 1985 Yarosh summarized the early work that established m6G as the alkylated base in DNA that was the most mutagenic and carcinogenic. [19] In 1994 Rasouli-Nia et al. [20] showed that about one mutation was induced for every eight unrepaired m6Gs in DNA. Mutations can cause progression to cancer by a process of natural selection.[ citation needed ]

Expression in cancer

Cancers deficient in MGMT
Cancer typeFrequency of deficiency in cancerFrequency of deficiency in adjacent field defect
Cervical [21] 61%39%
Colorectal40%-90% [22] [23] [24] [25] [26] 11%-34% [22] [23]
Colorectal with microsatellite instability [27] 70%60%
Esophageal adenocarcinoma71%-79% [28] [29] 89% [29]
Esophageal squamous cell carcinoma38%-96% [28] [30] [31] 65% [31]
Glioblastoma due to promoter methylation44%-59% [32] [33]
Head and neck squamous cell carcinoma54% [34]
Hepatocellular carcinoma (hepatitis C virus associated) [35] 68%65%
Larynx54%-61% [36] [37] 38% [37]
Stomach32%-88% [38] [39] 17%-78% [38] [39]
Thyroid [40] 87%

Epigenetic repression

Only a minority of sporadic cancers with a DNA repair deficiency have a mutation in a DNA repair gene. However, a majority of sporadic cancers with a DNA repair deficiency do have one or more epigenetic alterations that reduce or silence DNA repair gene expression. For example, in a study of 113 sequential colorectal cancers, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). [41]

MGMT can be epigenetically repressed in a number of ways. [42] When MGMT expression is repressed in cancers, this is often due to methylation of its promoter region. [42] However, expression can also be repressed by di-methylation of lysine 9 of histone 3 [43] or by over-expression of a number of microRNAs including miR-181d, miR-767-3p and miR-603. [42] [44] [45]

MGMT (O-6-methylguanine-DNA methyltransferase) is an important cancer biomarker because it is involved in the repair of DNA damage and is often silenced or inactivated in cancer cells. The loss of MGMT function leads to a higher rate of mutations, promoting the formation and progression of tumors. The presence or absence of MGMT expression in a cancer sample can indicate a patient's response to alkylating chemotherapy, which is a common treatment for certain types of cancer. Hence, MGMT can be used as a prognostic marker to predict the likelihood of treatment response and to guide the selection of appropriate therapies. A number of point-of-care devices are under development to monitor the methylation status of MGMT. [46]

Deficiency in field defects

Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors. Image of resected colon segment with cancer & 4 nearby polyps plus schematic of field defects with sub-clones.jpg
Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.

A field defect is an area or "field" of epithelium that has been preconditioned by epigenetic changes and/or mutations so as to predispose it towards development of cancer. A field defect is illustrated in the photo and diagram shown of a colon segment having a colon cancer and four small polyps within the same area as well. As pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. [47] Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion." [48] Similarly, Vogelstein et al. [49] point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.

In the Table above, MGMT deficiencies were noted in the field defects (histologically normal tissues) surrounding most of the cancers. If MGMT is epigenetically reduced or silenced, it would not likely confer a selective advantage upon a stem cell. However, reduced or absent expression of MGMT would cause increased rates of mutation, and one or more of the mutated genes may provide the cell with a selective advantage. The expression-deficient MGMT gene could then be carried along as a selectively neutral or only slightly deleterious passenger (hitch-hiker) gene when the mutated stem cell generates an expanded clone. The continued presence of a clone with an epigenetically repressed MGMT would continue to generate further mutations, some of which could produce a tumor.

Deficiency with exogenous damage

MGMT deficiency alone may not be sufficient to cause progression to cancer. Mice with a homozygous mutation in MGMT did not develop more cancers than wild-type mice when grown without stress. [50] However, stressful treatment of mice with azoxymethane and dextran sulphate caused more than four colonic tumors per MGMT mutant mouse, but less than one tumor per wild-type mouse. [51]

Repression in coordination with other DNA repair genes

In a cancer, multiple DNA repair genes are often found to be simultaneously repressed. [52] In one example, involving MGMT, Jiang et al. [53] conducted a study where they evaluated the mRNA expression of 27 DNA repair genes in 40 astrocytomas compared to normal brain tissues from non-astrocytoma individuals. Among the 27 DNA repair genes evaluated, 13 DNA repair genes, MGMT, NTHL1, OGG1, SMUG1,ERCC1, ERCC2 , ERCC3 , ERCC4 , MLH1 , MLH3 , RAD50 , XRCC4 and XRCC5 were all significantly down-regulated in all three grades (II, III and IV) of astrocytomas. The repression of these 13 genes in lower grade as well as in higher grade astrocytomas suggested that they may be important in early as well as in later stages of astrocytoma. In another example, Kitajima et al. [54] found that immunoreactivity for MGMT and MLH1 expression was closely correlated in 135 specimens of gastric cancer and loss of MGMT and hMLH1 appeared to be synchronously accelerated during tumor progression.

Deficient expression of multiple DNA repair genes are often found in cancers, [52] and may contribute to the thousands of mutations usually found in cancers (see mutation frequencies in cancers).

Interactions

O6-methylguanine-DNA methyltransferase has been shown to interact with estrogen receptor alpha. [55]

See also

Related Research Articles

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">Glioma</span> Tumour of the glial cells of the brain or spine

A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are cancerous but some are extremely slow to develop. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

<span class="mw-page-title-main">Neoplasm</span> Tumor or other abnormal growth of tissue

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, which may be called a tumour or tumor.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

<span class="mw-page-title-main">DNA mismatch repair</span> System for fixing base errors of DNA replication

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

<span class="mw-page-title-main">MSH2</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

<span class="mw-page-title-main">Cilengitide</span> Chemical compound

Cilengitide is a molecule designed and synthesized at the Technical University Munich in collaboration with Merck KGaA in Darmstadt. It is based on the cyclic peptide cyclo(-RGDfV-), which is selective for αv integrins, which are important in angiogenesis, and other aspects of tumor biology. Hence, it is under investigation for the treatment of glioblastoma, where it may act by inhibiting angiogenesis, and influencing tumor invasion and proliferation.

6-<i>O</i>-Methylguanine Chemical compound

6-O-Methylguanine is a derivative of the nucleobase guanine in which a methyl group is attached to the oxygen atom. It base-pairs to thymine rather than cytosine, causing a G:C to A:T transition in DNA.

<span class="mw-page-title-main">Temozolomide</span> Cancer medication

Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Field cancerization</span> Biological process

Field cancerization or field effect is a biological process in which large areas of cells at a tissue surface or within an organ are affected by carcinogenic alterations. The process arises from exposure to an injurious environment, often over a lengthy period.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation. DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

References

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