5-hydroxymethylcytosine

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Structural formula
Structure of 5-hydroxymethylcytosine
General
Surname 5-hydroxymethylcytosine
other names

4-Amino-5- (hydroxymethyl) -1 H -pyrimidin-2-one

Molecular formula C 5 H 7 N 3 O 2
External identifiers / databases
CAS number 1123-95-1
PubChem 70751
ChemSpider 63916
Wikidata Q238535
properties
Molar mass 141.13 g mol −1
Physical state

firmly

safety instructions
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

5-Hydroxymethylcytosine is a heterocyclic organic compound with a pyrimidine backbone. It is a derivative of the nucleic base cytosine with an additional hydroxymethyl group in position 5. It forms the nucleosides 5-hydroxymethylcytidine  (5hmC, hm 5 C) in the RNA and 5-hydroxymethyldeoxycytidine  ( 5-HOMe dC) in the DNA .

Biological importance

For a long time, 5-hydroxymethylcytosine was the only modified DNA base found in mammals alongside 5-methylcytosine . Therefore, 5-methylcytosine is often referred to as the fifth and 5-hydroxymethylcytosine is often referred to as the sixth base of DNA. Nowadays, other derivatives are already known, such as. B. 5-Formylcytosine (5fC) and 5-Carboxycytosine (5caC). 5-Hydroxymethylcytosine is formed in vivo post- replicatively (after DNA synthesis) from cytosine by adding a methyl group (see DNA methylation ) and subsequent oxidation . It is believed that 5-hydroxymethylcytosine, like 5-methylcytosine, plays an important role in epigenetics and is involved in switching genes on and off.

Occurrence

5-Hydroxymethylcytosine was discovered in bacteriophage DNA in the early 1950s . Here the hydroxymethyl group protects the phage DNA from degradation by bacterial restriction enzymes .

In 2009, two groups of researchers found that 5-hydroxymethylcytosine is also a component of mammalian DNA. It is now known that practically every mammalian cell contains 5-hydroxymethylcytosine and that the largest amounts are found in the central nervous system. The amount of 5-hydroxymethylcytosine increases during development but appears to be stable through adulthood. This has been shown in the cerebellum and hippocampus of mice. In line with this finding, embryonic and neuronal stem cells only contain small amounts of 5-hydroxymethylcytosine.

biosynthesis

In DNA, 5-hydroxymethylcytosine is the base of the nucleoside 5-hydroxymethylcytidine. It is formed from 5-methylcytidine by oxidation. This reaction is catalyzed by the iron (II) and ketoglutarate- dependent TET enzymes. In vitro , however, it could also be shown that methyltransferases can directly convert cytosine with formaldehyde , whereby 5-hydroxymethylcytosine is also formed.

function

The exact function of 5-hydroxymethylcytosine is currently unknown. However, it seems likely that the DNA base plays an important role in epigenetics and could have a decisive influence on gene expression . It was further speculated that 5-hydroxymethylcytosine is involved in active demethylation, the enzymatic cleavage of the methyl group from 5-methylcytosine. In the meantime, 5-formylcytosine, an intermediate of the postulated oxidative demethylation mechanism, has been detected in the DNA of embryonic stem cells. 5-Hydroxymethylcytosine could play a special role in the central nervous system, as it is there in particularly high amounts (~ 0.25% of all DNA bases).

Further effects

The discovery of 5-hydroxymethylcytosine calls into question studies of the distribution of 5-methylcytosine as standard detection methods such as bisulfite sequencing cannot differentiate between 5-hydroxymethylcytosine and 5-methylcytosine.

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ^ Warren RA: Modified bases in bacteriophage DNAs . In: Annu. Rev. Microbiol. . 34, 1980, pp. 137-158. doi : 10.1146 / annurev.mi.34.100180.001033 . PMID 7002022 .
  3. ↑ Wyatt GR, Cohen SS: A new pyrimidine base from bacteriophage nucleic acids . In: Nature . 170, No. 4338, December 1952, pp. 1072-1073. doi : 10.1038 / 1701072a0 . PMID 13013321 .
  4. ↑ Kriaucionis S, Heintz N: The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain . In: Science . 324, No. 5929, May 2009, pp. 929-930. doi : 10.1126 / science.1169786 . PMID 19372393 .
  5. ↑ a b Mamta Tahiliani, Kian Peng Koh, Yinghua Shen, William A. Pastor, Hozefa Bandukwala, Yevgeny Brudno, Suneet Agarwal, Lakshminarayan M. Iyer, David R. Liu, L. Aravind, Anjana Rao: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 . In: Science . 324, No. 5929, May 2009, pp. 930-935. doi : 10.1126 / science.1170116 . PMID 19372391 . PMC 2715015 (free full text).
  6. ↑ a b Martin Münzel, Daniel Globisch, Tobias Brückl, Mirko Wagner, Veronika Welzmiller, Stylianos Michalakis, Markus Müller, Martin Biel, Thomas Carell: Quantitative determination of the sixth DNA base hydroxymethylcytosine in the brain . In: Angew. Chem. . 122, No. 31, July 2010, pp. 5503-5505. doi : 10.1002 / anie.201002033 .
  7. ↑ Aleksandra Szwagierczak, Sebastian Bultmann, Christine S. Schmidt, Fabio Spada, Heinrich Leonhardt: Sensitive Enzymatic Quantification of 5-Hydroxymethylcytosine in Genomic DNA . In: Nucleic Acids Res . . 38, No. 19, October 2010, p. E181. doi : 10.1093 / nar / gkq684 .
  8. ^ A b Daniel Globisch, Martin Münzel, Markus Müller, Stylianos Michalakis, Mirko Wagner, Susanne Koch, Tobias Brückl, Martin Biel, Thomas Carell: Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates . In: PLoS ONE . 5, No. 12, December 2010, p. E15367. doi : 10.1371 / journal.pone.0015367 .
  9. ↑ Chun-Xiao Song, Keith E Szulwach, Ye Fu, Qing Dai, Chengqi Yi, Xuekun Li, Yujing Li, Chih-Hsin Chen, Wen Zhang, Xing Jian, Jing Wang, Li Zhang, Timothy J Looney, Baichen Zhang, Lucy A Godley, Leslie M Hicks, Bruce T Lahn, Peng Jin & Chuan H: Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine . In: Nat. Biotech. . 29, 2011, pp. 68-72. doi : 10.1038 / nbt.1732 .
  10. ↑ Zita Liutkevičiūtė, Gražvydas Lukinavičius, Viktoras Masevičius, Dalia Daujotytė & Saulius Klimašauskas: Cytosine-5-methyltransferases add aldehydes to DNA . In: Nat. Chem. Biol . 5, No. 6, June 2009, pp. 400-402. doi : 10.1038 / nchembio.172 .
  11. ↑ Pfaffeneder, Toni; Hackner, Benjamin, Truss, Matthias, Münzel, Martin, Müller, Markus, Deiml, Christian A., Hagemeier, Christian, Carell, Thomas: The Discovery of 5-Formylcytosine in Embryonic Stem Cell DNA. In: Angewandte Chemie , Int. Ed. 2011, Volume 123, Issue 31, pp. 7146–7150, doi: 10.1002 / anie.201103899 .
  12. ↑ Seung-Gi Jin, Swati Kadam, Gerd P. Pfeifer: Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine . In: Nucleic Acids Research . tape 38 , no. June 11 , 2010, p. e125 – e125 , doi : 10.1093 / nar / gkq223 .