View source for O-6-methylguanine-DNA methyltransferase

{{Infobox_gene}}
'''''O''<sup>6</sup>-alkylguanine DNA alkyltransferase''' (also known as '''AGT''', '''MGMT''' or '''AGAT''') is a [[protein]] that in humans is encoded by the ''O''<sup>6</sup>-methylguanine DNA methyltransferase (''MGMT'') [[gene]].<ref name="pmid2405387">{{cite journal | vauthors = Tano K, Shiota S, Collier J, Foote RS, Mitra S | title = Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O6-alkylguanine | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 2 | pages = 686–90  | date = January 1990 | pmid = 2405387 | pmc = 53330 | doi = 10.1073/pnas.87.2.686 }}</ref><ref name="pmid1635460">{{cite journal | vauthors = Natarajan AT, Vermeulen S, Darroudi F, Valentine MB, Brent TP, Mitra S, Tano K | title = Chromosomal localization of human O6-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization | journal = Mutagenesis | volume = 7 | issue = 1 | pages = 83–5  | date = January 1992 | pmid = 1635460 | doi = 10.1093/mutage/7.1.83 }}</ref>
O<sup>6</sup>-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion [[6-O-methylguanine|O<sup>6</sup>-methylguanine]] back to [[guanine]] and prevents mismatch and errors during [[DNA replication]] and [[Transcription (genetics)|transcription]]. Accordingly, loss of ''MGMT'' increases the carcinogenic risk in mice after exposure to alkylating agents.<ref name="pmid11023546">{{cite journal | vauthors = Shiraishi A, Sakumi K, Sekiguchi M | title = Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase | journal = Carcinogenesis | volume = 21 | issue = 10 | pages = 1879–83  | date = October 2000 | pmid = 11023546 | doi = 10.1093/carcin/21.10.1879 | url = http://carcin.oxfordjournals.org/content/21/10/1879.long }}</ref>
The two bacterial [[isozyme]]s are [[Ada (protein)|Ada]] and [[Ogt]].

== Function and mechanism==

{{enzyme|align=left
| Name = '''O''<sup>6</sup>-alkylguanine DNA alkyltransferase'
| EC_number = 2.1.1.63
| CAS_number = 77271-19-3
| IUBMB_EC_number = 
| GO_code = 
| image = 
| width = 
| caption = 
}}

Although [[alkylation|alkylating]] [[mutagen]]s preferentially modify the guanine base at the N7 position, ''O''<sup>6</sup>-alkyl-guanine is a major carcinogenic lesion in [[DNA]]. This [[DNA adduct]] is removed by the repair protein ''O''<sup>6</sup>-alkylguanine DNA alkyltransferase through an [[SN2 reaction|S<sub>N</sub>2 mechanism]]. This protein is not a true [[enzyme]] since it removes the alkyl group from the lesion in a [[stoichiometry|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]].<ref name="pmid17485253">{{cite journal | vauthors = Kaina B, Christmann M, Naumann S, Roos WP | title = MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents | journal = DNA Repair (Amst.) | volume = 6 | issue = 8 | pages = 1079–99  | date = August 2007 | pmid = 17485253 | doi = 10.1016/j.dnarep.2007.03.008 }}</ref>

[[File:6'-O-Methylguanosine.svg|200px|structural formula of 6-O-Methylguanosine]]<math>\mathrm{\ \xrightarrow{MGMT} }</math>[[File:Guanosin.svg|190px|structural formula of Guanosine]]
::Demethylation of [[6-O-methylguanine|6-O-methylguanosine]] to [[Guanosine]]

== Clinical significance ==

[[DNA methylation|Methylation]] of the gene's [[promoter (biology)|promoter]] may play a significant role in [[carcinogenesis]]. In patients with [[glioblastoma]], a severe type of brain tumor, the methylation state of the ''MGMT'' gene determined whether tumor cells would be responsive to [[temozolomide]]; if the promoter was methylated, temozolomide was more effective.<ref>{{cite journal | vauthors = Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R | title = MGMT gene silencing and benefit from temozolomide in glioblastoma | journal = N. Engl. J. Med. | volume = 352 | issue = 10 | pages = 997–1003 | year = 2005 | pmid = 15758010 | doi = 10.1056/NEJMoa043331 }}</ref> On a clinical level, this translates into a prolonged survival of glioblastoma patients with a methylated ''MGMT'' promoter. In addition, ''MGMT'' methylation can be used to predict patient survival in clinical prediction models.<ref>{{cite journal | vauthors = Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, Wesseling P, Hulsebos TJ, Troost D, van Tilborg AA, Leenstra S, Vandertop WP, Bardelli A, van Noorden CJ, Bleeker FE | title = The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone | journal = Neuro-oncology | volume = 16 | issue = 9 | pages = 1263–73 | year = 2014 | pmid = 24510240 | doi = 10.1093/neuonc/nou005 | pmc=4136888}}</ref> 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.<ref name="P1">{{cite journal | last1 = Preusser | first1 = M. | authorlink = Matthias Preusser | last2 = Janzer | first2 = Charles R. | last3 = Felsberg | first3 = J. | last4 = Reifenberger | first4 = G. | last5 = Hamou | first5 = M. F. | last6 = Diserens | first6 = A. C. | last7 = Stupp | first7 = R. | last8 = Gorlia | first8 = T. | last9 = Marosi | first9 = C. | last10 = Heinzl | first10 = H. | last11 = Hainfellner | first11 = J. A. | last12 = Hegi | first12 = M. | date = Oct 2008 | title = Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker | url = | journal = Brain Pathol | volume = 18 | issue = 4| pages = 520–532 | doi = 10.1111/j.1750-3639.2008.00153.x }}</ref>

''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.<ref>{{cite journal | vauthors = Chang AH, Stephan MT, Lisowski L, Sadelain M | title = Erythroid-specific human factor IX delivery from in vivo selected hematopoietic stem cells following nonmyeloablative conditioning in hemophilia B mice | journal = Mol. Ther. | volume = 16 | issue = 10 | pages = 1745–52 | year = 2008 | pmid = 18682698 | pmc = 2658893 | doi = 10.1038/mt.2008.161 }}</ref>

Mutagens in the environment,<ref name="pmid6386215">{{cite journal |vauthors=Bartsch H, Montesano R |title=Relevance of nitrosamines to human cancer |journal=Carcinogenesis |volume=5 |issue=11 |pages=1381–93 |year=1984 |pmid=6386215 |doi= 10.1093/carcin/5.11.1381|url=}}</ref> in tobacco smoke,<ref name="pmid21708177">{{cite journal |vauthors=Christmann M, Kaina B |title=O(6)-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke |journal=Mutat. Res. |volume=736 |issue=1–2 |pages=64–74 |year=2012 |pmid=21708177 |doi=10.1016/j.mrfmmm.2011.06.004 |url=}}</ref> food,<ref name="pmid23929436">{{cite journal |vauthors=Fahrer J, Kaina B |title=O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer |journal=Carcinogenesis |volume=34 |issue=11 |pages=2435–42 |year=2013 |pmid=23929436 |doi=10.1093/carcin/bgt275 |url=}}</ref> as well as endogenous metabolic products<ref name="pmid15123782">{{cite journal |vauthors=De Bont R, van Larebeke N |title=Endogenous DNA damage in humans: a review of quantitative data |journal=Mutagenesis |volume=19 |issue=3 |pages=169–85 |year=2004 |pmid=15123782 |doi= 10.1093/mutage/geh025|url=}}</ref> generate reactive electrophilic species that [[Alkylation|alkylate]] or  specifically [[Methylation|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.<ref name="pmid3883145">{{cite journal |vauthors=Yarosh DB |title=The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis |journal=Mutat. Res. |volume=145 |issue=1–2 |pages=1–16 |year=1985 |pmid=3883145 |doi= 10.1016/0167-8817(85)90034-3|url=}}</ref>  In 1994 Rasouli-Nia et al.<ref name="pmid7510369">{{cite journal |vauthors=Rasouli-Nia A, Sibghat-Ullah, Mirzayans R, Paterson MC, Day RS |title=On the quantitative relationship between O6-methylguanine residues in genomic DNA and production of sister-chromatid exchanges, mutations and lethal events in a Mer- human tumor cell line |journal=Mutat. Res. |volume=314 |issue=2 |pages=99–113 |year=1994 |pmid=7510369 |doi= 10.1016/0921-8777(94)90074-4|url=}}</ref> showed that about one mutation was induced for every eight unrepaired [[6-O-Methylguanine|m6Gs]] in DNA.  Mutations can cause progression to cancer by a process of natural selection.<ref>Bernstein C, Prasad AR, Nfonsam V, Bernstein H.  (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), {{ISBN|978-953-51-1114-6}}, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer</ref>

=== Expression in cancer ===

{| class="wikitable sortable"
|+'''Cancers deficient in MGMT'''
!width="200"|Cancer type
!width="100"|Frequency of deficiency in cancer
!width="100"|Frequency of deficiency in adjacent [[Neoplasm#Field defects|field defect]]
|-
|Cervical<ref name="pmid19513524">{{cite journal |vauthors=Iliopoulos D, Oikonomou P, Messinis I, Tsezou A |title=Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression |journal=Oncol. Rep. |volume=22 |issue=1 |pages=199–204 |year=2009 |pmid=19513524 |doi= 10.3892/or_00000425}}</ref>
|61%
|39%
|-
|Colorectal
|40%-90%<ref name=Shen>{{cite journal |vauthors=Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP |title=MGMT promoter methylation and field defect in sporadic colorectal cancer |journal=J. Natl. Cancer Inst. |volume=97 |issue=18 |pages=1330–8 |year=2005 |pmid=16174854 |doi=10.1093/jnci/dji275 |url=}}</ref><ref name=Lee>{{cite journal |vauthors=Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH |title=Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence |journal=Langenbecks Arch Surg |volume=396 |issue=7 |pages=1017–26 |year=2011 |pmid=21706233 |doi=10.1007/s00423-011-0812-9 |url=}}</ref><ref name="pmid20653064">{{cite journal |vauthors=Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, Kolios G |title=Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas |journal=World J. Gastroenterol. |volume=16 |issue=28 |pages=3553–60 |year=2010 |pmid=20653064 |pmc=2909555 |doi= 10.3748/wjg.v16.i28.3553|url=}}</ref><ref name="pmid23422094">{{cite journal |vauthors=Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S |title=Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer |journal=Clin. Cancer Res. |volume=19 |issue=8 |pages=2265–72 |year=2013 |pmid=23422094 |doi=10.1158/1078-0432.CCR-12-3518 |url=}}</ref><ref name="pmid23271133">{{cite journal |vauthors=Mokarram P, Zamani M, Kavousipour S, Naghibalhossaini F, Irajie C, Moradi Sarabi M, Hosseini SV |title=Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer |journal=Mol. Biol. Rep. |volume=40 |issue=5 |pages=3851–7 |year=2013 |pmid=23271133 |doi=10.1007/s11033-012-2465-3 |url=}}</ref>
|11%-34%<ref name=Shen /><ref name=Lee />
|-
|Colorectal with [[microsatellite instability]]<ref name="pmid20947886">{{cite journal |vauthors=Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, Lamri A, Hamelin R, Cosnes J, Oliveira C, Seruca R, Gaub MP, Legrain M, Collura A, Lascols O, Tiret E, Fléjou JF, Duval A |title=Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers |journal=Gut |volume=59 |issue=11 |pages=1516–26 |year=2010 |pmid=20947886 |doi=10.1136/gut.2009.194787 |url=}}</ref>
|70%
|60%
|-
|Esophageal adenocarcinoma
|71%-79%<ref name=Hasina /><ref name=Kuester>{{cite journal |vauthors=Kuester D, El-Rifai W, Peng D, Ruemmele P, Kroeckel I, Peters B, Moskaluk CA, Stolte M, Mönkemüller K, Meyer F, Schulz HU, Hartmann A, Roessner A, Schneider-Stock R |title=Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus |journal=Cancer Lett. |volume=275 |issue=1 |pages=117–26 |year=2009 |pmid=19027227 |pmc=4028828 |doi=10.1016/j.canlet.2008.10.009 |url=}}</ref>
|89%<ref name=Kuester />
|-
|Esophageal squamous cell carcinoma
|38%-96%<ref name=Hasina>{{cite journal |vauthors=Hasina R, Surati M, Kawada I, Arif Q, Carey GB, Kanteti R, Husain AN, Ferguson MK, Vokes EE, Villaflor VM, Salgia R |title=O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer |journal=J Carcinog |volume=12 |issue= |pages=20 |year=2013 |pmid=24319345 |pmc=3853796 |doi=10.4103/1477-3163.120632 |url=}}</ref><ref name="pmid21674174">{{cite journal |vauthors=Ling ZQ, Li P, Ge MH, Hu FJ, Fang XH, Dong ZM, Mao WM |title=Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer |journal=Dig. Dis. Sci. |volume=56 |issue=10 |pages=2992–3004 |year=2011 |pmid=21674174 |doi=10.1007/s10620-011-1774-z |url=}}</ref><ref name="pmid24366688">{{cite journal |vauthors=Su Y, Yin L, Liu R, Sheng J, Yang M, Wang Y, Pan E, Guo W, Pu Y, Zhang J, Liang G |title=Promoter methylation status of MGMT, hMSH2, and hMLH1 and its relationship to corresponding protein expression and TP53 mutations in human esophageal squamous cell carcinoma |journal=Med. Oncol. |volume=31 |issue=2 |pages=784 |year=2014 |pmid=24366688 |doi=10.1007/s12032-013-0784-4 |url=}}</ref><ref name="pmid24366688"/>
|65%<ref name="pmid24366688"/>
|-
|Glioblastoma due to promoter methylation
|44%-59%<ref name="pmid20167086">{{cite journal |vauthors=Morandi L, Franceschi E, de Biase D, Marucci G, Tosoni A, Ermani M, Pession A, Tallini G, Brandes A |title=Promoter methylation analysis of O6-methylguanine-DNA methyltransferase in glioblastoma: detection by locked nucleic acid based quantitative PCR using an imprinted gene (SNURF) as a reference |journal=BMC Cancer |volume=10 |issue= |pages=48 |year=2010 |pmid=20167086 |pmc=2843669 |doi=10.1186/1471-2407-10-48 |url=}}</ref><ref name="pmid22294349">{{cite journal |vauthors=Quillien V, Lavenu A, Karayan-Tapon L, Carpentier C, Labussière M, Lesimple T, Chinot O, Wager M, Honnorat J, Saikali S, Fina F, Sanson M, Figarella-Branger D |title=Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, MethyLight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients |journal=Cancer |volume=118 |issue=17 |pages=4201–11 |year=2012 |pmid=22294349 |doi=10.1002/cncr.27392 |url=}}</ref>
|
|-
|Head and neck squamous cell carcinoma
|54%<ref name="pmid22246327">{{cite journal |vauthors=Koutsimpelas D, Pongsapich W, Heinrich U, Mann S, Mann WJ, Brieger J |title=Promoter methylation of MGMT, MLH1 and RASSF1A tumor suppressor genes in head and neck squamous cell carcinoma: pharmacological genome demethylation reduces proliferation of head and neck squamous carcinoma cells |journal=Oncol. Rep. |volume=27 |issue=4 |pages=1135–41 |year=2012 |pmid=22246327 |pmc=3583513 |doi=10.3892/or.2012.1624 |url=}}</ref>
|
|-
|Hepatocellular carcinoma (hepatitis C virus associated)<ref name=Zekri>{{cite journal |vauthors=Zekri AR, Bahnasy AA, Shoeab FE, Mohamed WS, El-Dahshan DH, Ali FT, Sabry GM, Dasgupta N, Daoud SS |title=Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma |journal=J Adv Res |volume=5 |issue=1 |pages=27–40 |year=2014 |pmid=25685469 |pmc=4294722 |doi=10.1016/j.jare.2012.11.002 |url=}}</ref>
|68%
|65%
|-
|Larynx
|54%-61%<ref name="pmid23804521">{{cite journal |vauthors=Pierini S, Jordanov SH, Mitkova AV, Chalakov IJ, Melnicharov MB, Kunev KV, Mitev VI, Kaneva RP, Goranova TE |title=Promoter hypermethylation of CDKN2A, MGMT, MLH1, and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients |journal=Head Neck |volume=36 |issue=8 |pages=1103–8 |year=2014 |pmid=23804521 |doi=10.1002/hed.23413 |url=}}</ref><ref name=Paluszczak>{{cite journal |vauthors=Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W |title=Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa |journal=Oral Oncol. |volume=47 |issue=2 |pages=104–7 |year=2011 |pmid=21147548 |doi=10.1016/j.oraloncology.2010.11.006 |url=}}</ref>
|38%<ref name=Paluszczak />
|-
|Stomach
|32%-88%<ref name=Jin>{{cite journal |vauthors=Jin J, Xie L, Xie CH, Zhou YF |title=Aberrant DNA methylation of MGMT and hMLH1 genes in prediction of gastric cancer |journal=Genet. Mol. Res. |volume=13 |issue=2 |pages=4140–5 |year=2014 |pmid=24938706 |doi=10.4238/2014.May.30.9 |url=}}</ref><ref name="ZouXP">{{cite journal |vauthors=Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ |title=Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions |journal=Hum. Pathol. |volume=40 |issue=11 |pages=1534–42 |year=2009 |pmid=19695681 |doi=10.1016/j.humpath.2009.01.029 |url=}}</ref><ref name="ZouXP"/>
|17%-78%<ref name=Jin /><ref name="ZouXP"/><ref name=ZouXP />
|-
|Thyroid<ref name="pmid24388682">{{cite journal |vauthors=Mokhtar M, Kondo K, Namura T, Ali AH, Fujita Y, Takai C, Takizawa H, Nakagawa Y, Toba H, Kajiura K, Yoshida M, Kawakami G, Sakiyama S, Tangoku A |title=Methylation and expression profiles of MGMT gene in thymic epithelial tumors |journal=Lung Cancer |volume=83 |issue=2 |pages=279–87 |year=2014 |pmid=24388682 |doi=10.1016/j.lungcan.2013.12.004 |url=}}</ref>
|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 [[Epigenetics|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 [[Epigenetics|epigenetic]] alteration).<ref name="pmid15888787">{{cite journal |vauthors=Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I | title = O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions | journal = Gut | volume = 54 | issue = 6 | pages = 797–802 |date=June 2005 | pmid = 15888787 | pmc = 1774551 | doi = 10.1136/gut.2004.059535 }}</ref>

MGMT can be epigenetically repressed in a number of ways.<ref name=Cabrini>{{cite journal |vauthors=Cabrini G, Fabbri E, Lo Nigro C, Dechecchi MC, Gambari R |title=Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review) |journal=Int. J. Oncol. |volume=47 |issue=2 |pages=417–28 |year=2015 |pmid=26035292 |doi=10.3892/ijo.2015.3026 |pmc=4501657}}</ref>  When MGMT expression is repressed in cancers, this is often due to methylation of its promoter region.<ref name=Cabrini />  However, expression can also be repressed by di-methylation of lysine 9 of histone 3<ref name="pmid14647440">{{cite journal |vauthors=Nakagawachi T, Soejima H, Urano T, Zhao W, Higashimoto K, Satoh Y, Matsukura S, Kudo S, Kitajima Y, Harada H, Furukawa K, Matsuzaki H, Emi M, Nakabeppu Y, Miyazaki K, Sekiguchi M, Mukai T |title=Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer |journal=Oncogene |volume=22 |issue=55 |pages=8835–44 |year=2003 |pmid=14647440 |doi=10.1038/sj.onc.1207183 |url=}}</ref> or by over-expression of a number of microRNAs including miR-181d, miR-767-3p and miR-603.<ref name=Cabrini /><ref name="pmid24994119">{{cite journal |vauthors=Kushwaha D, Ramakrishnan V, Ng K, Steed T, Nguyen T, Futalan D, Akers JC, Sarkaria J, Jiang T, Chowdhury D, Carter BS, Chen CC |title=A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas |journal=Oncotarget |volume=5 |issue=12 |pages=4026–39 |year=2014 |pmid=24994119 |pmc=4147303 |doi= 10.18632/oncotarget.1974|url=}}</ref><ref name="pmid22570426">{{cite journal |vauthors=Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC |title=miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression |journal=Neuro-oncology |volume=14 |issue=6 |pages=712–9 |year=2012 |pmid=22570426 |pmc=3367855 |doi=10.1093/neuonc/nos089 |url=}}</ref>

=== Deficiency in field defects ===
[[File:Image of resected colon segment with cancer & 4 nearby polyps plus schematic of field defects with sub-clones.jpg|thumb|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 [[Neoplasm#Field defect|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.''<ref name="pmid21254148">{{cite journal | author = Rubin H | title = Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture | journal = BioEssays | volume = 33 | issue = 3 | pages = 224–31 |date=March 2011 | pmid = 21254148 | doi = 10.1002/bies.201000067 }}</ref>  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."<ref name="pmid10655514">{{cite journal |vauthors=Tsao JL, Yatabe Y, Salovaara R, Järvinen HJ, Mecklin JP, Aaltonen LA, Tavaré S, Shibata D | title = Genetic reconstruction of individual colorectal tumor histories | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 3 | pages = 1236–41 |date=February 2000 | pmid = 10655514 | pmc = 15581 | doi = 10.1073/pnas.97.3.1236 }}</ref> Similarly, Vogelstein et al.<ref name=Vogelstein>{{cite journal |vauthors=Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW | title = Cancer genome landscapes | journal = Science | volume = 339 | issue = 6127 | pages = 1546–58 |date=March 2013 | pmid = 23539594 | pmc = 3749880 | doi = 10.1126/science.1235122 }}</ref> 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.<ref name=Meira>{{cite journal |vauthors=Meira LB, Calvo JA, Shah D, Klapacz J, Moroski-Erkul CA, Bronson RT, Samson LD |title=Repair of endogenous DNA base lesions modulate lifespan in mice |journal=DNA Repair (Amst.) |volume=21 |issue= |pages=78–86 |year=2014 |pmid=24994062 |pmc=4125484 |doi=10.1016/j.dnarep.2014.05.012 |url=}}</ref>  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.<ref name="pmid20732909">{{cite journal |vauthors=Wirtz S, Nagel G, Eshkind L, Neurath MF, Samson LD, Kaina B |title=Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis |journal=Carcinogenesis |volume=31 |issue=12 |pages=2111–7 |year=2010 |pmid=20732909 |pmc=2994278 |doi=10.1093/carcin/bgq174 |url=}}</ref>

=== Repression in coordination with other DNA repair genes ===

In a cancer, multiple DNA repair genes are often found to be simultaneously repressed.<ref name=BernsteinC>{{cite journal |vauthors=Bernstein C, Bernstein H |title=Epigenetic reduction of DNA repair in progression to gastrointestinal cancer |journal=World J Gastrointest Oncol |volume=7 |issue=5 |pages=30–46 |year=2015 |pmid=25987950 |pmc=4434036 |doi=10.4251/wjgo.v7.i5.30 |url=}}</ref>  In one example, involving ''MGMT'', Jiang et al.<ref name="pmid17034947">{{cite journal |vauthors=Jiang Z, Hu J, Li X, Jiang Y, Zhou W, Lu D |title=Expression analyses of 27 DNA repair genes in astrocytoma by TaqMan low-density array |journal=Neurosci. Lett. |volume=409 |issue=2 |pages=112–7 |year=2006 |pmid=17034947 |doi=10.1016/j.neulet.2006.09.038 |url=}}</ref> 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]],'' ''[[Oxoguanine glycosylase|OGG1]],'' ''[[SMUG1]],'' ''ERCC1,'' ''[[ERCC2]]'', ''[[ERCC3]]'', ''[[ERCC4]]'', ''[[MLH1]]'', ''[[MLH3]]'', ''[[Rad50|RAD50]]'', ''[[DNA repair protein XRCC4|XRCC4]]'' and ''[[Ku80|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.<ref name="pmid12861399">{{cite journal |vauthors=Kitajima Y, Miyazaki K, Matsukura S, Tanaka M, Sekiguchi M |title=Loss of expression of DNA repair enzymes MGMT, hMLH1, and hMSH2 during tumor progression in gastric cancer |journal=Gastric Cancer |volume=6 |issue=2 |pages=86–95 |year=2003 |pmid=12861399 |doi=10.1007/s10120-003-0213-z |url=}}</ref> 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,<ref name=BernsteinC /> and may contribute to the thousands of mutations usually found in cancers (see [[Whole genome sequencing#Mutation frequencies|mutation frequencies in cancers]]).

== Interactions ==

''O''<sup>6</sup>-methylguanine-DNA methyltransferase has been shown to [[Protein-protein interaction|interact]] with [[estrogen receptor alpha]].<ref name="pmid11564893">{{cite journal | vauthors = Teo AK, Oh HK, Ali RB, Li BF | title = The modified human DNA repair enzyme O(6)-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage | journal = Mol. Cell. Biol. | volume = 21 | issue = 20 | pages = 7105–14  | date = October 2001 | pmid = 11564893 | pmc = 99886 | doi = 10.1128/MCB.21.20.7105-7114.2001 }}</ref>

== See also ==
*[[Ada (protein)|Ada]]
* [[Ogt]]
* [[6-O-Methylguanine]]
* [[DNA methyltransferase]]
* [[Methyltransferase]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Margison GP, Povey AC, Kaina B, Santibáñez Koref MF | title = Variability and regulation of O6-alkylguanine-DNA alkyltransferase | journal = Carcinogenesis | volume = 24 | issue = 4 | pages = 625–35 | year = 2003 | pmid = 12727789 | doi = 10.1093/carcin/bgg005 }}
{{refend}}

{{PDB Gallery|geneid=4255}}

{{Methyltransferases}}

[[Category:DNA repair]]