Affinage

MGMT

Methylated-DNA--protein-cysteine methyltransferase · UniProt P16455

Round 2 corrected
Length
207 aa
Mass
21.6 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MGMT is a suicide DNA repair enzyme that directly reverses O6-alkylguanine lesions by stoichiometrically transferring the alkyl group to its active-site Cys145, after which the inactivated protein is polyubiquitinated and degraded by the proteasome (PMID:2405387, PMID:8573590). Structural studies reveal that MGMT binds the DNA minor groove through a helix-turn-helix motif, flips the damaged nucleotide out of the duplex via Tyr114-assisted phosphate rotation, and executes methyl transfer at Cys145 (PMID:15221026). MGMT transcription is controlled by BRD4-dependent promoter activity, a distal MKI67-proximal enhancer, p53/mSin3A/HDAC1-mediated repression, and Fstl1/DIP2A/HDAC2-regulated chromatin acetylation, while post-translationally NDRG1 stabilizes MGMT protein and PARP1 PARylates MGMT to enhance repair through BER–direct-repair crosstalk (PMID:36513631, PMID:30054476, PMID:20525765, PMID:30542120, PMID:24367102, PMID:36242092). When MGMT is absent, unrepaired O6-methylguanine triggers MSH2/MSH6/MLH1/PMS2-dependent ATR-Chk1 checkpoint activation and apoptosis via ATM/ATR–p53/p73 signaling, and MGMT mRNA export is further enhanced under alkylation stress through CHK1-dependent DDX46 phosphorylation and LINC01956 structural remodeling (PMID:35388070, PMID:17485253, PMID:39356744).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1990 High

    Cloning of human MGMT established that O6-alkylguanine repair proceeds through a suicide mechanism in which the enzyme irreversibly transfers the alkyl group to an active-site cysteine, explaining the stoichiometric depletion of repair capacity in mammalian cells.

    Evidence Functional complementation cloning in E. coli ada− mutant with in vitro methyltransferase activity assay and Northern blot

    PMID:2405387

    Open questions at the time
    • Active-site cysteine not yet identified by mutagenesis
    • No structural information on substrate recognition
    • Post-translational fate of alkylated protein unknown
  2. 1996 High

    The question of how inactivated MGMT is cleared was resolved by showing that alkylated MGMT is polyubiquitinated and degraded via the ATP-dependent proteasome pathway, establishing a complete single-use repair cycle.

    Evidence Co-IP with anti-ubiquitin antibodies, cell-free ubiquitination assay, and temperature-sensitive ubiquitin-activating enzyme mutant (ts85 cells)

    PMID:8573590

    Open questions at the time
    • E3 ligase responsible for MGMT ubiquitination not identified
    • Whether sumoylation or other PTMs modulate degradation kinetics
  3. 2001 High

    Genetic epistasis experiments answered why MGMT loss is cytotoxic: unrepaired O6-methylguanine is processed by mismatch repair into a lethal signal, establishing the MGMT–MMR functional opposition that underlies alkylating-agent sensitivity.

    Evidence Cell viability and apoptosis assays in cells with modulated MGMT and MMR status; antisense and overexpression experiments

    PMID:11554312 PMID:13679151

    Open questions at the time
    • Exact nature of the MMR-generated lethal intermediate (futile cycling vs. strand break) not resolved
    • Whether MMR-independent killing occurs for specific adduct types
  4. 2004 High

    Crystal structures of MGMT bound to O6-methylguanine-containing DNA revealed the catalytic mechanism: minor-groove HTH binding, Tyr114-driven phosphate rotation to flip the damaged base, and direct alkyl transfer to Cys145, answering how a single protein accomplishes lesion recognition and repair in one step.

    Evidence X-ray crystallography of human MGMT–dsDNA complexes with substrate and crosslinked inhibitor; site-directed mutagenesis of Tyr114 and Cys145

    PMID:15221026

    Open questions at the time
    • Dynamics of nucleotide flipping in solution not captured by crystal structures
    • Structural basis for cooperative binding to DNA not fully resolved
  5. 2007 High

    The downstream signaling cascade following MGMT deficiency was mapped: unrepaired O6-methylguanine activates ATM/ATR–Chk1/Chk2–p53/p73 through MutSα-dependent MMR, engaging both death-receptor and mitochondrial apoptotic pathways, while O6-chloroethylguanine killing was shown to be MMR-independent.

    Evidence MGMT-modulated cell lines with epistasis across MMR-deficient lines; caspase activation and cytochrome c release assays

    PMID:17485253

    Open questions at the time
    • Relative contribution of p53 vs. p73 in different cell types unclear
    • Whether ATR-Chk1 signaling is the sole checkpoint engaged
  6. 2013 High

    NDRG1 was identified as a direct binding partner that stabilizes MGMT protein, revealing a post-translational mechanism by which the hypoxia–mTORC2–SGK1 axis sustains alkylating-agent resistance independently of MGMT transcription.

    Evidence Reciprocal Co-IP of NDRG1–MGMT; genetic knockdown/overexpression; glioma patient tissue and mouse xenograft validation

    PMID:24367102

    Open questions at the time
    • Structural basis of NDRG1–MGMT interaction unknown
    • Whether NDRG1 shields specific ubiquitination sites not determined
  7. 2018 High

    Multi-layered transcriptional regulation of MGMT was established: a distal enhancer between MKI67 and MGMT drives resistance-associated upregulation, while the Fstl1/DIP2A/HDAC2-DMAP1 axis controls H3K9 acetylation at the MGMT promoter, answering how MGMT expression is reactivated in resistant tumors despite promoter methylation.

    Evidence CRISPR enhancer deletion and dCas9 activation with ATAC-seq/ChIP-seq (enhancer study); Co-IP plus ChIP for H3K9Ac and epistasis with DIP2A knockdown (Fstl1 study); PDX models

    PMID:30054476 PMID:30542120

    Open questions at the time
    • Transcription factors binding the MKI67-proximal enhancer not fully catalogued
    • Whether enhancer activation is specific to recurrent GBM or a general mechanism
  8. 2019 High

    The checkpoint consequence of MGMT loss was refined: ATR-Chk1 activation by temozolomide requires MSH2, MSH6, MLH1, and PMS2 but not MSH3, delineating the specific MMR components that transduce unrepaired O6-methylguanine into checkpoint signaling and revealing ATR inhibitor vulnerability in MGMT-deficient tumors.

    Evidence Isogenic shRNA knockdown panel of individual MMR genes in MGMT-methylated GBM cells; phospho-ATR/Chk1 immunoblotting; ATR inhibitor treatment in vitro and in xenografts

    PMID:31273061 PMID:35388070

    Open questions at the time
    • Whether ATR inhibitor sensitivity extends to all MGMT-deficient tumor types
    • Role of secondary MMR-independent checkpoint pathways not excluded
  9. 2022 High

    BRD4 was shown to occupy the MGMT promoter and sustain Pol II–driven transcription, and PARP1 was found to PARylate MGMT in a DNA-independent manner enhancing its repair activity, revealing two previously unrecognized regulatory nodes—one transcriptional, one post-translational—that converge on MGMT output.

    Evidence ChIP for BRD4/Pol II with BET-inhibitor treatment and ectopic MGMT rescue (transcription); reciprocal Co-IP of PARP1–MGMT and in vitro PARylation plus repair activity assay (PTM)

    PMID:36242092 PMID:36513631

    Open questions at the time
    • Which PARylation sites on MGMT are functionally relevant not mapped
    • Whether BRD4-dependent transcription operates at the distal enhancer as well as the core promoter
  10. 2024 High

    A post-transcriptional resistance mechanism was uncovered: CHK1 phosphorylates DDX46, whose increased helicase activity remodels lncRNA LINC01956 to expose motifs that recruit MGMT mRNA for nuclear export, explaining how cytoplasmic MGMT protein rises during alkylation stress even in promoter-methylated tumors.

    Evidence RNA structural probing (SHAPE/DMS-MaPseq), RIP, ChIRP, phosphoproteomics of DDX46, CHK1 inhibitor rescue in PDX and tumor organoid models

    PMID:39356744

    Open questions at the time
    • Whether LINC01956-mediated export applies to non-glioblastoma contexts
    • Identity of the nuclear export receptor that recognizes remodeled LINC01956
    • Whether other RNA helicases can substitute for DDX46

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase(s) targeting alkylated MGMT for degradation, the structural basis of the NDRG1–MGMT and PARP1–MGMT interactions, and whether the transcriptional activator function of MGMT at the DUB3 promoter represents a widespread non-canonical role or a context-specific phenomenon.
  • E3 ligase for MGMT ubiquitination remains unidentified
  • No co-crystal structure of MGMT with any of its regulatory partners
  • Non-canonical transcription factor activity of MGMT at DUB3 awaits independent replication

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140097 catalytic activity, acting on DNA 3 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 1
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-4839726 Chromatin organization 4 R-HSA-8953854 Metabolism of RNA 1
Partners
ADRM1BRD4DDX46DIP2AHDAC8NDRG1PARP1TP53

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Human MGMT encodes a 22-kDa O6-methylguanine-DNA methyltransferase that repairs O6-alkylguanine adducts by stoichiometrically transferring the alkyl group to an active-site cysteine residue in a suicide reaction; the cDNA was cloned by functional rescue of an ada- E. coli host, and absence of MGMT expression in certain human cell lines was shown to result from absence of the gene or lack of its ~0.95-kb mRNA transcript. Functional complementation cloning in E. coli ada- mutant; in vitro methyltransferase activity assay; Northern blot analysis of MGMT mRNA Proceedings of the National Academy of Sciences of the United States of America High 2405387
1993 MGMT-mediated repair of O6-alkylguanine is a direct, single-step damage-reversal mechanism that inactivates the protein stoichiometrically (suicide enzyme), distinguishing it from catalytic repair enzymes; regulation of MGMT in mammalian cells involves both transcriptional control and post-translational protein stability. Biochemical assays of alkyltransferase activity; cell-based induction and depletion experiments reviewed with experimental data Progress in nucleic acid research and molecular biology High 8434121
1996 Inactivated MGMT (after reaction with O6-benzylguanine or BCNU) is degraded via the ubiquitin-proteasome pathway: alkylated MGMT becomes polyubiquitinated within hours of inactivation, and proteolysis is ATP/Mg2+-dependent and blocked in a ts85 cell line carrying a thermolabile ubiquitin-activating enzyme. Co-immunoprecipitation and immunoblotting with anti-ubiquitin and anti-MGMT antibodies; anti-ubiquitin immunoaffinity chromatography; cell-free ubiquitination assay; temperature-sensitive ubiquitin-activating enzyme mutant cell line (ts85) Biochemistry High 8573590
2001 O6-methylguanine induced by methylating agents is the major genotoxic and apoptotic lesion in MGMT-deficient cells; its cytotoxicity and apoptosis induction require functional mismatch repair (MMR), whereas N-alkylation damage repaired by BER becomes dominant when MGMT is highly expressed or when O6-methylguanine is scarce. Cell viability assays, apoptosis assays, and mutagenicity assays in cells with modulated MGMT and MMR activities; overexpression and antisense transfection experiments Progress in nucleic acid research and molecular biology High 11554312
2003 MGMT and MLH1 act in opposing pathways determining cell fate after alkylation damage: loss of MGMT sensitizes cells to MNU killing via MLH1-dependent apoptosis (caspase-3 induction), whereas additional Mlh1 deletion confers resistance and increases mutagenesis; MLH1 haploinsufficiency is sufficient to abolish apoptosis in Mgmt-/- cells, revealing a critical threshold for MMR-triggered cell death. Gene-targeted mouse cell lines (Mgmt-/-, Mlh1-/-, double knockout); cell survival assays; mutant frequency assays; caspase-3 immunoblotting; human MGMT cDNA overexpression DNA repair High 13679151
2004 Human AGT/MGMT binds DNA through its helix-turn-helix (HTH) motif in the minor groove (an unprecedented mode for an HTH domain), flips the O6-methylguanine nucleotide out of the duplex via phosphate rotation assisted by Tyr114, and transfers the alkyl group to the active-site Cys145; crystal structures with O6-methylguanine-containing dsDNA and a crosslinked inhibitor N1,O6-ethanoxanthosine define the substrate-binding and catalytic mechanism. X-ray crystallography of human AGT/MGMT bound to dsDNA containing O6-methylguanine or crosslinked to mechanistic inhibitor; biochemical mutagenesis of Tyr114 and Cys145 Nature structural & molecular biology High 15221026
2007 MGMT acts as a key cellular defense against O6-alkylating agents by directly reversing O6-methylguanine and O6-chloroethylguanine adducts; O6-methylguanine-induced clastogenicity and apoptosis require MutSα-dependent MMR and trigger the ATM/ATR–Chk1/Chk2–p53/p73 pathway with activation of both death receptor and mitochondrial apoptotic pathways, while O6-chloroethylguanine-induced killing is MMR-independent. MGMT-modulated cell lines (overexpression, knockdown, knockout); genotoxicity assays; apoptosis pathway analysis (caspase activation, cytochrome c release); epistasis with MMR-deficient lines DNA repair High 17485253
2010 Levetiracetam (LEV) inhibits MGMT expression by enhancing p53 binding to the MGMT promoter and recruiting the mSin3A/HDAC1 corepressor complex; chromatin immunoprecipitation confirmed increased p53 occupancy at the MGMT promoter, and the MGMT-inhibitory effect was abolished by knockdown of p53, mSin3A, or HDAC1. Chromatin immunoprecipitation (ChIP); siRNA knockdown of p53, mSin3A, HDAC1; RT-PCR and western blot for MGMT mRNA and protein; patient biopsy samples pre- and post-LEV treatment Neuro-oncology Medium 20525765
2013 The mTOR target NDRG1 physically binds and stabilizes MGMT protein, protecting it from degradation; NDRG1 expression is induced by hypoxia (via HIF-1α), irradiation, corticosteroids, and chronic alkylating agent exposure through HIF-1α, p53, and mTORC2/SGK1 pathways, and NDRG1-dependent MGMT stabilization mediates resistance to alkylating chemotherapy but not radiotherapy. Co-immunoprecipitation of NDRG1 and MGMT; genetic knockdown/overexpression; glioma patient post-treatment tissue analysis; mouse xenograft models; pathway inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 24367102
2016 MGMT undergoes post-translational regulation by ubiquitination (targeting inactivated protein for proteasomal degradation), sumoylation, and glutathionylation; the active-site Cys145 is exploited by thiol-reactive compounds (e.g., disulfiram, dithiocarbamate derivatives) to potently inactivate and deplete MGMT independent of the O6-benzylguanine pseudosubstrate strategy. Biochemical assays of MGMT ubiquitination, sumoylation, and glutathionylation; in vitro MGMT inactivation assays with thiol-reactive compounds; cell-based MGMT depletion assays Mini reviews in medicinal chemistry Medium 26202203
2018 An enhancer element located between the MKI67 and MGMT gene promoters is activated in temozolomide-resistant glioblastoma; forced activation of this enhancer increases MGMT expression, while CRISPR-mediated deletion of the enhancer dramatically reduces MGMT and Ki67 expression, increases TMZ sensitivity, and impairs proliferation. CRISPR/dCas9-based enhancer activation; CRISPR deletion of enhancer; ChIP-seq; ATAC-seq; RNA-seq in patient-derived xenograft lines and recurrent tumor samples Nature communications High 30054476
2018 Fstl1 competes with DIP2A for binding, blocking DIP2A nuclear translocation; nuclear DIP2A normally associates with the HDAC2-DMAP1 complex to promote H3K9 deacetylation at the MGMT promoter, suppressing MGMT transcription. Fstl1 overexpression prevents this, increases H3K9 acetylation at the MGMT promoter, upregulates MGMT, and drives TMZ resistance; DIP2A depletion abolished the effects of Fstl1 on MGMT expression. Co-immunoprecipitation (Fstl1-DIP2A interaction); ChIP for H3K9Ac at MGMT promoter; siRNA knockdown and overexpression; nuclear fractionation; in vivo xenograft experiments Oncogene High 30542120
2019 MGMT transcriptionally activates DUB3, which in turn deubiquitinates and stabilizes MCL1 in ovarian cancer cells; the MGMT inhibitor PaTrin-2 suppresses this MGMT-DUB3-MCL1 axis and overcomes chemoresistance; HDAC inhibitors activate MGMT/DUB3 expression, and combined HDACi + PaTrin-2 is synergistic. Co-immunoprecipitation (DUB3-MCL1 interaction); ubiquitination assays; ChIP (MGMT binding at DUB3 promoter); siRNA knockdown; in vitro and in vivo tumor models Proceedings of the National Academy of Sciences of the United States of America High 30718431
2019 HDAC8 regulates MGMT protein levels in glioblastoma through interaction with the proteasome receptor ADRM1; pharmacological inhibition or shRNA knockdown of HDAC8 decreases MGMT levels independent of MGMT promoter methylation status; TMZ treatment disrupts the HDAC8-ADRM1 interaction selectively in TMZ-sensitive cells, suggesting this pathway is inactivated in resistant cells. Co-immunoprecipitation (HDAC8-ADRM1); HDAC8-specific inhibitor (PCI34051) and shRNA knockdown; western blot for MGMT; cell viability and cell cycle assays; DNA damage marker (γH2AX) Genes & cancer Medium 31798765
2019 In MGMT-deficient tumor cells, temozolomide activates the ATR-Chk1 checkpoint axis in an MGMT-dependent manner; this sensitizes MGMT-deficient cells to ATR inhibitors both in vitro and in vivo, establishing functional crosstalk between MGMT-mediated repair and the ATR checkpoint pathway. Isogenic MGMT-proficient and MGMT-deficient cell lines; ATR inhibitor treatment; phospho-Chk1 immunoblotting; cell cycle analysis; in vivo xenograft experiments across multiple tumor types Cancer research High 31273061
2022 PARP1 and MGMT interact directly in a DNA-independent manner; upon DNA alkylation damage, PARP1 also PARylates MGMT, forming a novel DNA damage-inducible PARP1-MGMT complex that enhances O6-methylguanine repair; this catalytic interaction reveals functional crosstalk between BER (PARP1) and direct repair (MGMT) pathways. Clinically relevant chronic TMZ exposure induced MGMT PARylation and increased PARP1-MGMT chromatin binding. Co-immunoprecipitation (PARP1-MGMT); in vitro PARylation assay; chromatin fractionation after TMZ treatment; MGMT repair activity assays comparing PARylated vs. unmodified MGMT Journal of hematology & oncology High 36242092
2022 BET protein BRD4 binds the MGMT promoter and supports MGMT transcription; BET inhibitors reduce BRD4 and RNA Pol II occupancy at the MGMT promoter, attenuate MGMT expression (including TMZ-induced MGMT upregulation), and sensitize glioblastoma cells to TMZ; ectopic MGMT expression from an unrelated promoter rescues the effect, confirming specificity for MGMT transcriptional regulation. ChIP for BRD4 and Pol II at MGMT promoter; BET inhibitor treatment (JQ1 and others); ectopic MGMT overexpression rescue experiment; γH2AX measurement; MSH2/MSH6 expression monitoring; glioblastoma-derived sphere models Cell death & disease High 36513631
2022 MSH2, MSH6, MLH1, and PMS2 (but not MSH3) are required for ATR pathway activation in response to TMZ in MGMT-promoter-methylated glioblastoma cells; isogenic MMR knockdown cell lines showed that these specific MMR proteins mediate the ATR-Chk1 signaling axis triggered by unrepaired O6-methylguanine. Isogenic shRNA knockdowns of individual MMR genes (MSH2, MSH6, MSH3, MLH1, PMS2) in MGMT-methylated glioblastoma cells; phospho-ATR and phospho-Chk1 immunoblotting after TMZ treatment Scientific reports High 35388070
2023 The small molecule EPIC-0412 epigenetically silences MGMT by disrupting binding of the ATF3-phospho-p65-HDAC1 complex at the MGMT promoter region, as demonstrated by ChIP and Co-IP assays; this reduces MGMT expression and sensitizes TMZ-resistant glioblastoma cells to temozolomide. Chromatin immunoprecipitation (ChIP) for ATF3, p-p65, HDAC1 at MGMT promoter; Co-immunoprecipitation of transcription factor complex; RNA immunoprecipitation (RIP); ChIRP; animal xenograft experiments Neuro-oncology Medium 36272139
2024 In MGMT-promoter-methylated glioblastoma, TMZ activates CHK1, which phosphorylates the RNA helicase DDX46; phosphorylated DDX46 undergoes a conformational change increasing its helicase activity, which remodels the tertiary structure of lncRNA LINC01956 to expose binding motifs that recruit MGMT mRNA to the RNA nuclear export machinery, increasing cytoplasmic MGMT abundance and conferring TMZ resistance; CHK1 inhibition abolishes this structural remodeling and resensitizes cells to TMZ. RNA immunoprecipitation (RIP); ChIRP; mass spectrometry; structural probing assays (SHAPE/DMS-MaPseq) of LINC01956; phosphoproteomic analysis of DDX46; CHK1 inhibitor (SRA737) treatment; patient-derived xenograft and tumor organoid models Science translational medicine High 39356744

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England journal of medicine 5676 15758010
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2005 Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics 1390 15765097
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2014 Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. The Lancet. Oncology 854 25163906
2008 Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 681 18757334
2008 MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 663 18445844
2004 Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clinical cancer research : an official journal of the American Association for Cancer Research 662 15041700
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA repair 504 17485253
2009 Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 490 19805672
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 MGMT promoter methylation and field defect in sporadic colorectal cancer. Journal of the National Cancer Institute 390 16174854
2002 Clinical relevance of MGMT in the treatment of cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 362 11981013
2009 MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro-oncology 338 20150378
2005 Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 333 16195237
2008 Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro-oncology 318 18952979
1990 Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O6-alkylguanine. Proceedings of the National Academy of Sciences of the United States of America 298 2405387
2005 Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clinical cancer research : an official journal of the American Association for Cancer Research 295 16203797
2012 MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta neuropathologica 267 22810491
2004 DNA binding and nucleotide flipping by the human DNA repair protein AGT. Nature structural & molecular biology 258 15221026
2011 Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. International journal of cancer 254 21425258
2020 MGMT Status as a Clinical Biomarker in Glioblastoma. Trends in cancer 253 32348734
2010 Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem cells (Dayton, Ohio) 247 20309962
2012 Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma. AJNR. American journal of neuroradiology 242 22322613
2017 The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials. Journal of cellular physiology 238 28266716
2005 Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. International journal of cancer 234 15455350
2008 Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 225 18509181
2012 Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. International journal of cancer 223 22139906
2018 A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nature communications 209 30054476
2006 Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 209 16609022
2009 MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 205 19901104
2008 PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia (New York, N.Y.) 204 18516290
2020 O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy. Frontiers in oncology 200 32010632
2016 A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta neuropathologica communications 199 27503138
2006 Targeted modulation of MGMT: clinical implications. Clinical cancer research : an official journal of the American Association for Cancer Research 194 16428468
1996 Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumor cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochemistry 192 8573590
2013 Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 190 24068788
2008 Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain pathology (Zurich, Switzerland) 183 18400046
1993 Regulation of repair of alkylation damage in mammalian genomes. Progress in nucleic acid research and molecular biology 183 8434121
2013 mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proceedings of the National Academy of Sciences of the United States of America 152 24367102
2010 Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-oncology 127 20525765
2015 IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 124 26503470
2013 Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. OncoTargets and therapy 123 24109190
2010 Absence of the MGMT protein as well as methylation of the MGMT promoter predict the sensitivity for temozolomide. British journal of cancer 97 20517307
2008 MGMT immunohistochemical expression and promoter methylation in human glioblastoma. Applied immunohistochemistry & molecular morphology : AIMM 96 18091318
2008 Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 93 18997474
2013 MiR-221/222 target the DNA methyltransferase MGMT in glioma cells. PloS one 88 24147153
2012 Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. Journal of biomedicine & biotechnology 86 22701311
2001 BER, MGMT, and MMR in defense against alkylation-induced genotoxicity and apoptosis. Progress in nucleic acid research and molecular biology 78 11554312
2010 MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro-oncology 75 20179017
2005 Epigenetic silencing of the MGMT gene in cancer. Biochemistry and cell biology = Biochimie et biologie cellulaire 71 16094446
2019 MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America 70 30718431
2013 Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells. Chinese journal of cancer 69 23958055
2010 Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres. Clinical cancer research : an official journal of the American Association for Cancer Research 67 21097691
2017 Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer. International journal of molecular sciences 66 28353639
2012 Volumetric and MGMT parameters in glioblastoma patients: survival analysis. BMC cancer 64 22214427
2006 Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Current opinion in pharmacology 62 16777483
2002 Frequent promoter hypermethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene in testicular cancer. Oncogene 59 12483540
2019 Changes of O6-Methylguanine DNA Methyltransferase (MGMT) Promoter Methylation in Glioblastoma Relapse-A Meta-Analysis Type Literature Review. Cancers 52 31766430
2012 MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC cancer 52 22672670
2019 Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors. Cancer research 51 31273061
2008 Role of mismatch repair and MGMT in response to anticancer therapies. Anti-cancer agents in medicinal chemistry 49 18473722
2023 A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma. Neuro-oncology 48 36272139
2018 Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation. Neuro-oncology 48 29016808
2015 Treatment considerations for MGMT-unmethylated glioblastoma. Current neurology and neuroscience reports 48 25394859
2018 Fstl1/DIP2A/MGMT signaling pathway plays important roles in temozolomide resistance in glioblastoma. Oncogene 45 30542120
2011 MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. Journal of neuro-oncology 45 21311951
2010 MGMT immunoexpression in aggressive pituitary adenoma and carcinoma. Pituitary 45 20740317
2023 Quercetin induces MGMT+ glioblastoma cells apoptosis via dual inhibition of Wnt3a/β-Catenin and Akt/NF-κB signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 42 37451151
2021 Regulation of temozolomide resistance in glioma cells via the RIP2/NF-κB/MGMT pathway. CNS neuroscience & therapeutics 40 33460245
2019 Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival. British journal of cancer 39 31413318
2011 A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy. Biochemical and biophysical research communications 39 21329652
2003 Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis. DNA repair 39 13679151
2011 O(6)-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke. Mutation research 38 21708177
2007 Genetic association and functional studies of major polymorphic variants of MGMT. DNA repair 38 17569599
2020 Inhibition of MGMT-mediated autophagy suppression decreases cisplatin chemosensitivity in gastric cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 32007918
2019 Profound, durable and MGMT-independent sensitivity of glioblastoma cells to cyclin-dependent kinase inhibition. International journal of cancer 33 30549269
2019 HDAC8 affects MGMT levels in glioblastoma cell lines via interaction with the proteasome receptor ADRM1. Genes & cancer 33 31798765
2013 MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. World journal of gastroenterology 33 23716983
2012 Methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene in triple-negative breast cancer patients. Breast cancer research and treatment 33 22228432
2024 MGMT in TMZ-based glioma therapy: Multifaceted insights and clinical trial perspectives. Biochimica et biophysica acta. Molecular cell research 32 38242327
2017 Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma. Journal of translational medicine 32 28314386
2011 Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 21274674
2002 O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives. Japanese journal of cancer research : Gann 30 11802813
2019 O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET). Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 29 30824408
2012 Strategies to improve the killing of tumors using temozolomide: targeting the DNA repair protein MGMT. Current medicinal chemistry 29 22788764
2009 Association between MGMT promoter hypermethylation and p53 mutation in glioblastoma. Cancer investigation 29 19544111
2020 The Role of miRNA for the Treatment of MGMT Unmethylated Glioblastoma Multiforme. Cancers 28 32354046
2012 O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary corticotroph adenomas. Neurosurgery 28 21822153
2019 Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 27 31740551
2014 Role of MGMT as biomarker in colorectal cancer. World journal of clinical cases 27 25516857
2024 Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma. Journal of neuro-oncology 26 38277015
2016 Posttranslational Regulation of O(6)-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers. Mini reviews in medicinal chemistry 24 26202203
2009 Effects of O6-methylguanine-DNA methyltransferase (MGMT) polymorphisms on cancer: a meta-analysis. Mutagenesis 24 19892775
2019 IKBKE enhances TMZ-chemoresistance through upregulation of MGMT expression in glioblastoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 23 31865606
2017 Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 28848211
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2023 Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma. Neoplasia (New York, N.Y.) 21 37634280
2017 MGMT hypomethylation is associated with DNA damage in workers exposed to low-dose benzene. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 21 28001451
2014 Immunohistochemical evaluation of O6 -methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma. Neuropathology : official journal of the Japanese Society of Neuropathology 20 24397721
2012 Progress in high-throughput assays of MGMT and APE1 activities in cell extracts. Mutation research 20 22609488
2022 BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression. Cell death & disease 19 36513631
2020 Blocking MAPK/ERK pathway sensitizes hepatocellular carcinoma cells to temozolomide via downregulating MGMT expression. Annals of translational medicine 19 33209885
2015 Multidrug Efflux Pumps Attenuate the Effect of MGMT Inhibitors. Molecular pharmaceutics 19 26379107
2007 Lung cancer risk and variation in MGMT activity and sequence. DNA repair 19 17569600
2022 Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma. Scientific reports 18 35388070
2022 PARP1-MGMT complex underpins pathway crosstalk in O6-methylguanine repair. Journal of hematology & oncology 18 36242092
2020 Critical appraisal of MGMT in digestive NET treated with alkylating agents. Endocrine-related cancer 18 32698158
2019 MGMT Testing in Glioblastomas: Pitfalls and Opportunities. American journal of clinical oncology 18 30444735
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2008 Absence of MGMT promoter methylation in endometrial cancer. Gynecologic oncology 17 18973931
2020 Tim-3 Expression and MGMT Methylation Status Association With Survival in Glioblastoma. Frontiers in pharmacology 16 33041828
2019 Downregulation of MGMT promotes proliferation of intrahepatic cholangiocarcinoma by regulating p21. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 16 31264147
2018 O6-Methyguanine-DNA Methyl Transferase (MGMT) Promoter Methylation in Serum DNA of Iranian Patients with Colorectal Cancer. Asian Pacific journal of cancer prevention : APJCP 16 29801405
2016 Aberrant Methylation of MGMT Promoter in HNSCC: A Meta-Analysis. PloS one 16 27657735
2014 Aberrant DNA methylation of MGMT and hMLH1 genes in prediction of gastric cancer. Genetics and molecular research : GMR 16 24938706
2006 hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 16 16607377
1990 The control of O6-methylguanine-DNA methyltransferase (MGMT) activity in mammalian cells: a pre-molecular view. Mutation research 16 2233795
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2013 Toward a Molecular Classification of Colorectal Cancer: The Role of MGMT. Frontiers in oncology 14 24151575
2024 Dynamic structural remodeling of LINC01956 enhances temozolomide resistance in MGMT-methylated glioblastoma. Science translational medicine 13 39356744
2022 Clinical strategies to manage adult glioblastoma patients without MGMT hypermethylation. Journal of Cancer 13 34976195
2022 Organochlorine pesticides may induce leukemia by methylation of CDKN2B and MGMT promoters and histone modifications. Gene 13 36261081
2019 Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer. Cancer letters 13 30677446
2017 MGMT gene variants, temozolomide myelotoxicity and glioma risk. A concise literature survey including an illustrative case. Journal of chemotherapy (Florence, Italy) 13 28436299
2018 MGMT gene promoter methylation and its correlation with clinicopathological parameters in glioblastomas. Neurology India 12 30038102
2018 Pyrosequencing Analysis of MGMT Promoter Methylation in Meningioma. Cancer genomics & proteomics 12 30194078