Genomes and Genes
dna modification methylases
Summary: Enzymes that are part of the restriction-modification systems. They are responsible for producing a species-characteristic methylation pattern, on either adenine or cytosine residues, in a specific short base sequence in the host cell's own DNA. This methylated sequence will occur many times in the host-cell DNA and remain intact for the lifetime of the cell. Any DNA from another species which gains entry into a living cell and lacks the characteristic methylation pattern will be recognized by the restriction endonucleases of similar specificity and destroyed by cleavage. Most have been studied in bacterial systems, but a few have been found in eukaryotic organisms.
- Malygin E, Hattman S. DNA methyltransferases: mechanistic models derived from kinetic analysis. Crit Rev Biochem Mol Biol. 2012;47:97-193 pubmed publisher..Thus, this review considers in turn studies carried out with the most consistently and extensively investigated [N6-adenine]-, [N4-cytosine]- and [C5-cytosine]-DNA MTases. ..
- Bady P, Sciuscio D, Diserens A, Bloch J, van den Bent M, Marosi C, et al. 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 Neuropathol. 2012;124:547-60 pubmed publisher
- Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707-15 pubmed publisher..MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Merck Sharp & Dohme. ..
- Kim Y, Kim S, Cho J, Kim J, Chang J, Kim D, et al. MGMT gene promoter methylation as a potent prognostic factor in glioblastoma treated with temozolomide-based chemoradiotherapy: a single-institution study. Int J Radiat Oncol Biol Phys. 2012;84:661-7 pubmed publisher..2 months. We confirmed that MGMT gene methylation is a potent prognostic factor in patients with GBM. Our results suggest that early postoperative radiotherapy and a high total/subtotal resection rate might further improve the outcome. ..
- Berghoff A, Preusser M. Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients--yes, but how?. Clin Neuropathol. 2012;31:405-8 pubmed..Such studies need to take into account the considerable variation in pre-analytical tissue handling (e.g., tissue fixation conditions) between laboratories. ..
- Sun W, Zaboli D, Wang H, Liu Y, Arnaoutakis D, Khan T, et al. Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer. Clin Cancer Res. 2012;18:1082-91 pubmed publisher..Detection of promoter hypermethylation of TIMP3 in pretreatment salivary rinse is independently associated with local recurrence-free survival in patients with HNSCC and may be a valuable salivary rinse biomarker for HNSCC recurrence. ..
- Mellai M, Monzeglio O, Piazzi A, Caldera V, Annovazzi L, Cassoni P, et al. MGMT promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors. J Neurooncol. 2012;107:617-31 pubmed publisher..In low-grade gliomas, MGMT hypermethylation, but not MGMT protein expression, was associated with a trend, only, toward better survival, in contrast with GBMs, for which it had favorable prognostic significance. ..
- Happold C, Roth P, Wick W, Schmidt N, Florea A, Silginer M, et al. Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem. 2012;122:444-55 pubmed publisher..In conclusion, we demonstrate that different molecular mechanisms may contribute to the development of acquired TMZ resistance in glioma cells, indicating the need to develop distinct strategies to overcome resistance. ..
- Sanders Y, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman D, et al. Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:525-35 pubmed publisher..Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF. ..
- Schäfer A, Teufel J, Ringel F, Bettstetter M, Hoepner I, Rasper M, et al. Aldehyde dehydrogenase 1A1--a new mediator of resistance to temozolomide in glioblastoma. Neuro Oncol. 2012;14:1452-64 pubmed publisher..0001). ALDH1A1 is a new mediator for resistance of GBM to temozolomide and a reliable predictor of clinical outcome and may serve as a potential target to improve treatment of human GBM. ..
- Rao D, Dryden D, Bheemanaik S. Type III restriction-modification enzymes: a historical perspective. Nucleic Acids Res. 2014;42:45-55 pubmed publisher..A growing number of these enzymes are being subjected to biochemical and genetic studies, which, when combined with ongoing structural analyses, promise to provide details for mechanisms of DNA recognition and catalysis. ..
- Seshasayee A, Singh P, Krishna S. Context-dependent conservation of DNA methyltransferases in bacteria. Nucleic Acids Res. 2012;40:7066-73 pubmed publisher..Despite their sporadic occurrence, conserved R-M systems are present in strength in two highly transformable genera, in which they may contribute to selection against integration of foreign DNA. ..
- Eglen R, Reisine T. Screening for compounds that modulate epigenetic regulation of the transcriptome: an overview. J Biomol Screen. 2011;16:1137-52 pubmed publisher..This review focuses on the rationale for drug development of these enzymes, as well the utility of HTS methods used in identifying and optimizing novel selective compounds that modulate epigenetic control of the human transcriptome. ..
- Srikhanta Y, Fox K, Jennings M. The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes. Nat Rev Microbiol. 2010;8:196-206 pubmed publisher..The wide distribution of phase-variable mod family genes indicates that this may be a common strategy used by host-adapted bacterial pathogens to randomly switch between distinct cell types. ..
- van den Bent M, Dubbink H, Marie Y, Brandes A, Taphoorn M, Wesseling P, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16:1597-604 pubmed publisher..IDH1 mutations were strongly associated with 1p/19q codeletion and MGMT promoter methylation. ..
- Hiraki M, Kitajima Y, Sato S, Mitsuno M, Koga Y, Nakamura J, et al. Aberrant gene methylation in the lymph nodes provides a possible marker for diagnosing micrometastasis in gastric cancer. Ann Surg Oncol. 2010;17:1177-86 pubmed publisher..Three of 20 cases (15%) exhibited both the M/M pattern and positive mRNA. The methylation analysis revealed the clinical feasibility of detecting occult neoplastic cells in the regional LNs. ..
- Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer. 2012;131:1342-50 pubmed publisher..Taken together, MGMT promoter methylation may be a useful biomarker to stratify elderly glioblastoma patients for treatment with versus without alkylating agent CT. ..
- Balañá C, Carrato C, Ramirez J, Cardona A, Berdiel M, Sanchez J, et al. Tumour and serum MGMT promoter methylation and protein expression in glioblastoma patients. Clin Transl Oncol. 2011;13:677-85 pubmed publisher..Serum-based MGMT methylation analysis offers a promising alternative to tumor-based MGMT analysis in cases where tissue samples are unavailable. ..
- Abouzeid H, Kassem A, Abdel Wahab A, El Mezayen H, Sharad H, Abdel Rahman S. Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour Biol. 2011;32:845-52 pubmed publisher..Hypermethylation of MGMT and HIC-1 genes plays an important role in the initiation of disease especially ulcerative colitis-carcinoma pathway. ..
- O Mara T, Ferguson K, Fahey P, Marquart L, Yang H, Lissowska J, et al. CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk. Twin Res Hum Genet. 2011;14:328-32 pubmed publisher..Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer. ..
- Kristensen L, Nielsen H, Hager H, Hansen L. Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP. Lung Cancer. 2011;71:130-6 pubmed publisher..In conclusion, methylation of the MGMT promoter occurs in a subset of MPM patients and is associated with the T allele of the MGMT rs16906252 SNP. However, complete silencing of MGMT in MPM is a rare event. ..
- El Hindy N, Adamzik M, Lambertz N, Bachmann H, Worm K, Egensperger R, et al. Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme. J Cancer Res Clin Oncol. 2010;136:1423-9 pubmed publisher..1, P = 0.004) as an independent negative prognostic factor for 2-year survival according to the GNB3 825 TT genotype reference group. Our data suggest an association of the GNB3 825TT genotype and better survival in patients with GBM. ..
- Mulholland S, Pearson D, Hamoudi R, Malley D, Smith C, Weaver J, et al. MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations. Int J Cancer. 2012;131:1104-13 pubmed publisher..We suggest that MGMT methylation may be one of the earliest events in the development of astrocytic and oligodendroglial tumors. ..
- Natsume A, Kondo Y, Ito M, Motomura K, Wakabayashi T, Yoshida J. Epigenetic aberrations and therapeutic implications in gliomas. Cancer Sci. 2010;101:1331-6 pubmed publisher..Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia. ..
- Rivera A, Pelloski C, Gilbert M, Colman H, De La Cruz C, Sulman E, et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol. 2010;12:116-21 pubmed publisher..Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM. ..
- Fabi A, Metro G, Vidiri A, Lanzetta G, Carosi M, Telera S, et al. Low-dose fotemustine for recurrent malignant glioma: a multicenter phase II study. J Neurooncol. 2010;100:209-15 pubmed publisher..The role of MGMT gene promoter methylation status in relation to sensitivity to fotemustine is still unclear and needs further evaluation in future clinical trials. ..
- Tran H, Kim H, Lee I, Kim Y, Ahn J, Yang D, et al. DNA methylation changes following 5-azacitidine treatment in patients with myelodysplastic syndrome. J Korean Med Sci. 2011;26:207-13 pubmed publisher..The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments. ..
- Spiegl Kreinecker S, Pirker C, Filipits M, Lötsch D, Buchroithner J, Pichler J, et al. O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients. Neuro Oncol. 2010;12:28-36 pubmed publisher..00, 95% CI 0.45-2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients. ..
- Yang X, Lay F, Han H, Jones P. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci. 2010;31:536-46 pubmed publisher..This review delineates the latest cancer epigenetic models, the recent discovery of hypomethylation agents as well as their application in the clinic. ..
- Hamilton M, Roldan G, Magliocco A, McIntyre J, Parney I, Easaw J. Determination of the methylation status of MGMT in different regions within glioblastoma multiforme. J Neurooncol. 2011;102:255-60 pubmed publisher..Although the reason for this is unclear, we postulate that the timing from resection to fixation or the process of fixation itself may potentially alter methylation status in paraffin-embedded tumors. ..
- Weller M, Stupp R, Reifenberger G, Brandes A, van den Bent M, Wick W, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine?. Nat Rev Neurol. 2010;6:39-51 pubmed publisher..Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice. ..
- Uno M, Oba Shinjo S, Camargo A, Moura R, Aguiar P, Cabrera H, et al. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma. Clinics (Sao Paulo). 2011;66:1747-55 pubmed..Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue. ..
- Chen H, Lu H, Yang J, Kuo S, Lo C, Yang M, et al. The novel quinolone CHM-1 induces DNA damage and inhibits DNA repair gene expressions in a human osterogenic sarcoma cell line. Anticancer Res. 2010;30:4187-92 pubmed..Taken together, the results indicate that CHM-1 caused DNA damage and reduced DNA repair genes in U-2 OS cells, which may be the mechanism for CHM-1-inhibited cell growth and induction of apoptosis. ..
- Slaby O, Lakomy R, Fadrus P, Hrstka R, Kren L, Lzicarova E, et al. MicroRNA-181 family predicts response to concomitant chemoradiotherapy with temozolomide in glioblastoma patients. Neoplasma. 2010;57:264-9 pubmed..Our data indicate for the first time that expression levels of miR-181b and miR-181c could serve as a predictive marker of response to RT/TMZ therapy in glioblastoma patients. ..
- Quick A, Patel D, Hadziahmetovic M, Chakravarti A, Mehta M. Current therapeutic paradigms in glioblastoma. Rev Recent Clin Trials. 2010;5:14-27 pubmed..This article will review the current therapies for GBM and the investigation of new molecular and targeted therapies, such as EGFR inhibitors, mTOR/PI3Kinase inhibitors, and anti-angiogenesis agents. ..
- Loh Y, Mitrou P, Wood A, Luben R, McTaggart A, Khaw K, et al. SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Cancer Epidemiol. 2011;35:369-74 pubmed publisher..A combination of variants of the SMAD7 SNPs may be associated with increased cancer risk in this study population. However, these findings need to be replicated in larger studies and in studies of specific cancer sites. ..
- Shah N, Lin B, Sibenaller Z, Ryken T, Lee H, Yoon J, et al. Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM. PLoS ONE. 2011;6:e16146 pubmed publisher..Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting. ..
- Madhusoodanan U, Rao D. Diversity of DNA methyltransferases that recognize asymmetric target sequences. Crit Rev Biochem Mol Biol. 2010;45:125-45 pubmed publisher..The rapid progress made by the genome sequencing of bacteria and archaea may accelerate the identification and study of species- and strain-specific MTases of host-adapted bacteria and their roles in pathogenic mechanisms. ..
- Leng S, Bernauer A, Hong C, Do K, Yingling C, Flores K, et al. The A/G allele of rs16906252 predicts for MGMT methylation and is selectively silenced in premalignant lesions from smokers and in lung adenocarcinomas. Clin Cancer Res. 2011;17:2014-23 pubmed publisher..Moreover, TMZ treatment may benefit a subset of lung cancer patients methylated for MGMT. ..
- Minniti G, Salvati M, Arcella A, Buttarelli F, D Elia A, Lanzetta G, et al. Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol. 2011;102:311-6 pubmed publisher..004 and P = 0.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ. ..
- Costa B, Smith J, Chen Y, Chen J, Phillips H, Aldape K, et al. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res. 2010;70:453-62 pubmed publisher..Our findings suggest a transcriptional pathway through which PI3K activates oncogenic HOXA expression with implications for mTOR or PI3K targeted therapies. ..
- Songtao Q, Lei Y, Si G, Yanqing D, Huixia H, Xuelin Z, et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci. 2012;103:269-73 pubmed publisher..Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma. ..
- Shen B, Xu D, Chan S, Zheng Y, Zhu Z, Xu S, et al. Characterization and crystal structure of the type IIG restriction endonuclease RM.BpuSI. Nucleic Acids Res. 2011;39:8223-36 pubmed publisher..DNA binding and cleavage must involve large movements of the endonuclease and TRD domains, that are probably tightly coordinated and coupled to target site methylation status. ..
- Mokrishcheva M, Solonin A, Nikitin D. Fused eco29kIR- and M genes coding for a fully functional hybrid polypeptide as a model of molecular evolution of restriction-modification systems. BMC Evol Biol. 2011;11:35 pubmed publisher..Lastly, this study demonstrates that protein fusion may change biochemical properties of the involved enzymes, thus giving a starting point for their further evolutionary divergence. ..
- Hibi K, Sakata M, Yokomizo K, Kitamura Y, Sakuraba K, Shirahata A, et al. Methylation of the MGMT gene is frequently detected in advanced gastric carcinoma. Anticancer Res. 2009;29:5053-5 pubmed..0470), lymph node metastasis (p=0.0470), and TNM stage (p=0.0377) (Table I). Moreover, a trend was shown toward large maximal tumor size in methylated tumors (p=0.134). MGMT was more frequently methylated in advanced gastric carcinomas. ..