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5-Methylcytosine is a methylated form of the DNA base cytosine that may be involved in the regulation of gene transcription. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered (the study of this is part of the field of epigenetics). 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.

In 5-methylcytosine, a methyl group, is attached to the 5th atom in the 6-atom ring (counting counterclockwise from the NH nitrogen at the six o'clock position, not the 2 o'clock). This methyl group distinguishes 5-methylcytosine from cytosine.

Discovery

While trying to isolate the bacterial toxin responsible for tuberculosis, W.G. Ruppel isolated a novel nucleic acid named tuberculinic acid in 1898 from Tubercle bacillus.^[1] The nucleic acid was found to be unusual, in that it contained in addition to thymine, guanine and cytosine, a methylated nucleotide. In 1925, Johnson and Coghill successfully detected a minor amount of a methylated cytosine derivative as a product of hydrolysis of tuberculinic acid with sulfuric acid.^[2]^[3] This report was severely criticized because their identification based solely on the optical properties of the crystalline picrate, and other scientists failed to reproduce the same result.^[4] But the existence was ultimately proved a fact in 1948, when Hotchkiss separated the nucleic acids of DNA from calf thymus using paper chromatography, by which he detected a unique methylated cytosine, quite distinct from conventional cytosine and uracil.^[5] After seven decades, it turned out that it is also a common feature in different RNA molecules, although the precise role is uncertain.^[6]

In vivo

5-Methylcytosine is an epigenetic modification formed by the action of DNA methyltransferases.

The function of this chemical varies significantly among species:^[7]

In bacteria, 5-methylcytosine can be found at a variety of sites, and is often used as a marker to protect DNA from being cut by native methylation-sensitive restriction enzymes.
In plants, 5-methylcytosine occurs at CpG, CpHpG and CpHpH sequences (where H = A, C or T).
In fungi and animals, 5-methylcytosine predominantly occurs at CpG dinucleotides. Most eukaryotes methylate only a small percentage of these sites, but 70-80% of CpG cytosines are methylated in vertebrates.

While spontaneous deamination of cytosine forms uracil, which is recognized and removed by DNA repair enzymes, deamination of 5-methylcytosine forms thymine. This conversion of a DNA base from cytosine (C) to thymine (T) can result in a transition mutation. In addition, active enzymatic deamination of cytosine or 5-methylcytosine by the APOBEC family of cytosine deaminases could have beneficial implications on various cellular processes as well as on organismal evolution.^[8] The implications of deamination on 5-hydroxymethylcytosine, on the other hand, remains less understood.

In vitro

The NH₂ group can be removed (deamination) from 5-methylcytosine to form thymine with use of reagents such as nitrous acid; cytosine deaminates to uracil under similar conditions.

Deamination of 5-methylcytosine to thymine

5-Methylcytosine is resistant to deamination by bisulfite treatment, which deaminates cytosine residues. This property is often exploited to analyze DNA cytosine methylation patterns with bisulfite sequencing.^[9]

References

^ Matthews AP (2012). Physiological Chemistry. Williams & Wilkins Company/RareBooksClub.com. p. 167. ISBN 1130145379.
^ Johnson TB, Coghill RD (1925). "The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the Tubercle bacillus". J Am Chem Soc 47 (11): 2838–2844. doi:10.1021/ja01688a030.
^ Grosjean H (2009). Nucleic Acids Are Not Boring Long Polymers of Only Four Types of Nucleotides: A Guided Tour. Landes Bioscience.
^ Vischer E, Zamenhof S, Chargaff E (1949). "Microbial nucleic acids: the desoxypentose nucleic acids of avian tubercle bacilli and yeast". J Biol Chem 77 (1): 429–438. PMID 18107446.
^ Hotchkiss RD (1948). "The quantitative separation of purines, pyrimidines and nucleosides by paper chromatography". J Biol Chem 175 (1): 315–332. PMID 18107446.
^ Squires JE, Patel HR, Nousch M, Sibbritt T, Humphreys DT, Parker BJ, Suter CM, Preiss T. (2012). "Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA". Nucleic Acids Res 40 (11): 5023–5033. doi:10.1093/nar/gks144. PMC 3367185. PMID 22344696.
^ Colot V, Rossignol JL (1999). "Eukaryotic DNA methylation as an evolutionary device". BioEssays 21 (5): 402–411. doi:10.1002/(SICI)1521-1878(199905)21:5<402::AID-BIES7>3.0.CO;2-B. PMID 10376011.
^ Chahwan R., Wontakal S.N., and Roa S. (2010). "Crosstalk between genetic and epigenetic information through cytosine deamination". Trends in Genetics 26 (10): 443–448. doi:10.1016/j.tig.2010.07.005. PMID 20800313.
^ Clark SJ, Harrison J, Paul CL, Frommer M (1994). "High sensitivity mapping of methylated cytosines". Nucleic Acids Res. 22 (15): 2990–2997. doi:10.1093/nar/22.15.2990. PMC 310266. PMID 8065911.

Literature

Griffiths, Anthony J. F. (1999). An Introduction to genetic analysis. San Francisco: W.H. Freeman. Chapter 15: Gene Mutation. ISBN 0-7167-3520-2. (available online at the United States National Center for Biotechnology Information)

English Journal

Electrochemical evaluation of DNA methylation level based on the stoichiometric relationship between purine and pyrimidine bases.

Wang P, Chen H, Tian J, Dai Z, Zou X.SourceJiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, PR China. wangpo@jsnu.edu.cn
Biosensors & bioelectronics.Biosens Bioelectron.2013 Jul 15;45:34-9. doi: 10.1016/j.bios.2013.01.057. Epub 2013 Feb 7.
An efficient electrochemical approach for the evaluation of DNA methylation level was proposed according to the oxidation signal of DNA bases at an overoxidized polypyrrole (PPyox) directed multiwalled carbon nanotubes (MWNTs) film modified glassy carbon electrode (GCE). The PPyox/MWNTs/GCE exhibite
PMID 23454340

Epigenetic Modifications of Nrf2 by 3,3'-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors.

Wu TY, Khor TO, Su ZY, Saw CL, Shu L, Cheung KL, Huang Y, Yu S, Kong AN.SourceCenter for Cancer Prevention Research, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.
The AAPS journal.AAPS J.2013 Jul;15(3):864-74. doi: 10.1208/s12248-013-9493-3. Epub 2013 May 9.
3,3'-diindolylmethane (DIM) is currently being investigated in many clinical trials including prostate, breast, and cervical cancers and has been shown to possess anticancer effects in several in vivo and in vitro models. Previously, DIM has been reported to possess cancer chemopreventive effects in
PMID 23658110

Label-Free and Selective Photoelectrochemical Detection of Chemical DNA Methylation Damage Using DNA Repair Enzymes.

Wu Y, Zhang B, Guo LH.SourceState Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
Analytical chemistry.Anal Chem.2013 Jul 1. [Epub ahead of print]
Exogenous chemicals may produce DNA methylation that is potentially toxic to living systems. Methylated DNA bases are difficult to detect with biosensors because the methyl group is small and chemically inert. In this report, a label-free photoelectrochemical sensor was developed for the selective d
PMID 23777269

Japanese Journal

メチル化DNA結合タンパク質MBD4の可塑的な塩基認識機構

有吉眞理子,大谷淳二,白川昌宏
薬学雑誌. 乙号 135(1), 3-9, 2015
… One of the MBD proteins, MBD4, uniquely contains a C-terminal glycosylation domain together with an N-terminal MBD, and functions as a mismatch DNA repair enzyme specific for T/G or U/G mismatch bases generated by spontaneous deamination of 5-methylcytosine. … The base excision activity of MBD4 is also implicated in active DNA demethylation initiated by the conversion of 5-methylcytosine to thymine by deaminases. …
NAID 130004756466

CGmCGCG is a versatile substrate with which to evaluate Tet protein activity.

Kizaki Seiichiro,Sugiyama Hiroshi
Organic & biomolecular chemistry 12(1), 104-107, 2014-01-07
… Tet family proteins have the ability to convert 5-methylcytosine (mC) to 5-hydroxymethylcytosine, and further to 5-formylcytosine and 5-carboxycytosine. …
NAID 120005527982

Distinct Global DNA Methylation Status in B-Cell Lymphomas : Immunohistochemical Study of 5-Methylcytosine and 5-Hydroxymethylcytosine

, ,
Journal of Clinical and Experimental Hematopathology 54(1), 67-73, 2014
… These mutations are proposed to inhibit conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), leading to global accumulation of 5 mC. …
NAID 130004886478

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リンク元

「メチルシトシン」

5-Methylcytosine
Names
	IUPAC name 4-amino-5-methyl-3H-pyrimidin-2-one
Identifiers
CAS Registry Number	554-01-8
ChEBI	CHEBI:27551
ChemSpider	58551
	InChI InChI=1S/C5H7N3O/c1-3-2-7-5(9)8-4(3)6/h2H,1H3,(H3,6,7,8,9) ; Key: LRSASMSXMSNRBT-UHFFFAOYSA-N ; InChI=1/C5H7N3O/c1-3-2-7-5(9)8-4(3)6/h2H,1H3,(H3,6,7,8,9); Key: LRSASMSXMSNRBT-UHFFFAOYAO ;
Jmol-3D images	Image; Image
KEGG	C02376
MeSH	5-Methylcytosine
PubChem	65040
	SMILES O=C1/N=C\C(=C(\N)N1)C ; Cc1cnc(=O)[nH]c1N ;
UNII	6R795CQT4H
Properties
Chemical formula	C5H7N3O
Molar mass	125.13 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

　　[★]

英: methylcytosine, MeCyt
関: シトシン

[1] Matthews AP (2012). Physiological Chemistry. Williams & Wilkins Company/RareBooksClub.com. p. 167. ISBN 1130145379.

[2] Johnson TB, Coghill RD (1925). "The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the Tubercle bacillus". J Am Chem Soc 47 (11): 2838–2844. doi:10.1021/ja01688a030.

[3] Grosjean H (2009). Nucleic Acids Are Not Boring Long Polymers of Only Four Types of Nucleotides: A Guided Tour. Landes Bioscience.

[4] Vischer E, Zamenhof S, Chargaff E (1949). "Microbial nucleic acids: the desoxypentose nucleic acids of avian tubercle bacilli and yeast". J Biol Chem 77 (1): 429–438. PMID 18107446.

[5] Hotchkiss RD (1948). "The quantitative separation of purines, pyrimidines and nucleosides by paper chromatography". J Biol Chem 175 (1): 315–332. PMID 18107446.

[6] Squires JE, Patel HR, Nousch M, Sibbritt T, Humphreys DT, Parker BJ, Suter CM, Preiss T. (2012). "Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA". Nucleic Acids Res 40 (11): 5023–5033. doi:10.1093/nar/gks144. PMC 3367185. PMID 22344696.

[7] Colot V, Rossignol JL (1999). "Eukaryotic DNA methylation as an evolutionary device". BioEssays 21 (5): 402–411. doi:10.1002/(SICI)1521-1878(199905)21:5<402::AID-BIES7>3.0.CO;2-B. PMID 10376011.

[Chahwan_R.2C_Wontakal_SN.2C_and_Roa_S-8] Chahwan R., Wontakal S.N., and Roa S. (2010). "Crosstalk between genetic and epigenetic information through cytosine deamination". Trends in Genetics 26 (10): 443–448. doi:10.1016/j.tig.2010.07.005. PMID 20800313.

[9] Clark SJ, Harrison J, Paul CL, Frommer M (1994). "High sensitivity mapping of methylated cytosines". Nucleic Acids Res. 22 (15): 2990–2997. doi:10.1093/nar/22.15.2990. PMC 310266. PMID 8065911.

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methylcytosine