6-''O''-Methylguanine is a derivative of the

nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...

guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...

in which a

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...

is attached to the oxygen atom. It base-pairs to

thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidi ...

rather than

cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an ...

, 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 ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

. NOC are

alkylating agents Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...

formed by the reaction of nitrite or other nitrogen oxides with secondary

amines In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

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 ''O''6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the ''O''6-methylguanine DNA methyltransferase (''MGMT'') gene. O6-methylguanine DNA methyltransferase is crucial for genome stabi ...

(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 Sister chromatid exchange (SCE) is the exchange of genetic material between two identical sister chromatids. It was first discovered by using the Giemsa staining method on one chromatid belonging to the sister chromatid complex before anaphase i ...

, or apoptosis. These effects are due to interaction of the

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

pathway with 6-''O''-methylguanine, and also depend on signaling network activation, led by early ATM, H2AX, CHK1 and p53 phosphorylation.

References

{{DEFAULTSORT:Methylguanine, 6-O- Nucleobases Purines

Formation

Repair and carcinogenicity

Mutagenicity

Other effects

See also

References