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6-O-Methylguanine

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6-O-Methylguanine
Names
Preferred IUPAC name 6-Methoxy-9H-purin-2-amine
Other names 6-Methoxyguanine; O-Methylguanine; 2-Amino-6-methoxypurine
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.111.933 Edit this at Wikidata
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C6H7N5O/c1-12-5-3-4(9-2-8-3)10-6(7)11-5/h2H,1H3,(H3,7,8,9,10,11)Key: BXJHWYVXLGLDMZ-UHFFFAOYSA-N
  • InChI=1/C6H7N5O/c1-12-5-3-4(9-2-8-3)10-6(7)11-5/h2H,1H3,(H3,7,8,9,10,11)Key: BXJHWYVXLGLDMZ-UHFFFAOYAR
SMILES
  • COC1=NC(=NC2=C1NC=N2)N
Properties
Chemical formula C6H7N5O
Molar mass 165.156 g·mol
Melting point >300 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). ☒N verify (what is  ?) Infobox references
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.

Formation

6-O-Methylguanine is formed in DNA by alkylation of the oxygen atom of guanine, most often by N-nitroso compounds (NOC) and sometimes due to methylation by other compounds such as endogenous S-adenosyl methionine. NOC are alkylating agents formed by the reaction of nitrite or other nitrogen oxides with secondary amines and N-alkylamides, yielding N-alkylnitrosamines and N-alkylnitrosamides.

NOC are found in some foods (bacon, sausages, cheese) and tobacco smoke, and are formed in the gastrointestinal tract, especially after consumption of red meat. In addition, endogenous nitric oxide levels were found to be enhanced under chronic inflammatory conditions, and this could favor NOC formation in the large intestine.

Repair and carcinogenicity

Repair of 6-O-methylguanine in DNA is primarily carried out by O-6-methylguanine-DNA methyltransferase (MGMT). Epigenetic reductions in MGMT expression are one of the most frequent DNA repair defects, associated with carcinogenesis. (Also see MGMT expression in cancer.)

Mutagenicity

In 1985 Yarosh summarized the early work that established 6-O-methylguanine as the alkylated base in DNA that was the most mutagenic and carcinogenic. In 1994 Rasouli-Nia et al. showed that about one mutation was induced for every eight unrepaired 6-O-Methylguanines in DNA.

About one third of the time 6-O-methylguanine mispairs during replication, leading to the incorporation of dTMP rather than dCMP. 6-O-methylguanine is therefore a mutagenic nucleobase. However, the mutagenicity of a particular 6-O-methylguanine base depends on the sequence in which it is embedded.

Other effects

Unrepaired 6-O-methylguanine can also lead to cell cycle arrest, sister chromatid exchange, or apoptosis. These effects are due to interaction of the DNA mismatch repair pathway with 6-O-methylguanine, and also depend on signaling network activation, led by early ATM, H2AX, CHK1 and p53 phosphorylation.

See also

EMS mutagenesis

Temozolomide

References

  1. 6-O-Methylguanine at Sigma-Aldrich
  2. ^ Fahrer J, Kaina B (2013). "O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer". Carcinogenesis. 34 (11): 2435–42. doi:10.1093/carcin/bgt275. PMID 23929436.
  3. De Bont R, van Larebeke N (2004). "Endogenous DNA damage in humans: a review of quantitative data". Mutagenesis. 19 (3): 169–85. doi:10.1093/mutage/geh025. PMID 15123782.
  4. Bernstein C, Bernstein H (2015). "Epigenetic reduction of DNA repair in progression to gastrointestinal cancer". World J Gastrointest Oncol. 7 (5): 30–46. doi:10.4251/wjgo.v7.i5.30. PMC 4434036. PMID 25987950.
  5. Yarosh DB (1985). "The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis". Mutat. Res. 145 (1–2): 1–16. doi:10.1016/0167-8817(85)90034-3. PMID 3883145.
  6. Rasouli-Nia A, Sibghat-Ullah, Mirzayans R, Paterson MC, Day RS (1994). "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". Mutat. Res. 314 (2): 99–113. doi:10.1016/0921-8777(94)90074-4. PMID 7510369.
  7. Abbott PJ, Saffhill R (1979). "DNA synthesis with methylated poly(dC-dG) templates. Evidence for a competitive nature to miscoding by O(6)-methylguanine". Biochim. Biophys. Acta. 562 (1): 51–61. doi:10.1016/0005-2787(79)90125-4. PMID 373805.
  8. Georgiadis P, Smith CA, Swann PF (1991). "Nitrosamine-induced cancer: selective repair and conformational differences between O6-methylguanine residues in different positions in and around codon 12 of rat H-ras". Cancer Res. 51 (21): 5843–50. PMID 1933853.
  9. ^ Noonan EM, Shah D, Yaffe MB, Lauffenburger DA, Samson LD (2012). "O6-Methylguanine DNA lesions induce an intra-S-phase arrest from which cells exit into apoptosis governed by early and late multi-pathway signaling network activation". Integrative Biology. 4 (10): 1237–55. doi:10.1039/c2ib20091k. PMC 3574819. PMID 22892544.
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