Chemistry:5-Formylcytosine

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5-Formylcytosine
Skeletal formula of 5-Formylcytosine
Names
Preferred IUPAC name
4-Amino-2-oxo-1,2-dihydropyrimidine-5-carbaldehyde
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
Properties
C5H5N3O2
Molar mass 139.11 g/mol
Appearance yellow solid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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5-Formylcytosine (5fC) is a pyrimidine nitrogen base derived from cytosine. In the context of nucleic acid chemistry and biology, it is regarded as an epigenetic marker. Discovered in 2011 in mammalian embryonic stem cells by Thomas Carell's research group[1] the modified nucleoside was more recently confirmed to be relevant both as an intermediate in the active demethylation pathway and as a standalone epigenetic marker.[2] In mammals, 5fC is formed by oxidation of 5-Hydroxymethylcytosine (5hmC) a reaction mediated by TET enzymes.[3] Its molecular formula is C5H5N3O2.[4]

Localization

Similarly to the related cytosine modifications 5-Methylcytosine (5mC) and 5hmC, 5fC is broadly distributed across the mammalian genome, although it is much more rarely occurring.[5] The specific concentration values vary significantly depending on the cell type.[6] 5fC can be aberrantly expressed in distinct sets of tissue that can indicate different tumor onsets and canceration.[7]

Functions

The exact functions of 5fC have not been yet precisely defined, although it is likely to play key roles in at least two distinct frameworks. Firstly, 5fC serves as an intermediate of the active demethylation pathway, a process that contributes to the DNA maintenance and integrity by replacing 5mC with canonical cytosine. A central dilemma regarding 5fC (and epigenetics in general) is how reader proteins recognise their substrates with such high specificity over the overwhelming background. Thymine-DNA glycosylase (TDG), a protein which is involved in the removal of 5fC from DNA in mammals, is especially interesting in this context.[8] Secondly, 5fC can exist as an independent, stable modification, but its role in this context is still blurry. [2]

5fC impact on DNA structure and flexibility

The understanding of the impact of 5fC on DNA physical properties is to date limited. Recent studies have reported contradictory findings regarding the structural impact of 5fC on DNA.[9][10] On the other hand, several researchers working independently have identified 5fC to distinctly increase DNA flexibility.[11][12] 5fC also curtails DNA double helix stability and increases base pair opening.[13]

See also

References

  1. ↑ Pfaffeneder, Toni; Hackner, Benjamin; Truß, Matthias; Münzel, Martin; Müller, Markus; Deiml, Christian A.; Hagemeier, Christian; Carell, Thomas (2011). "The Discovery of 5-Formylcytosine in Embryonic Stem Cell DNA". Angewandte Chemie International Edition 50 (31): 7008–7012. doi:10.1002/anie.201103899. ISSN 1521-3773. PMID 21721093. 
  2. ↑ 2.0 2.1 Bachman, Martin; Uribe-Lewis, Santiago; Yang, Xiaoping; Burgess, Heather E.; Iurlaro, Mario; Reik, Wolf; Murrell, Adele; Balasubramanian, Shankar (2015). "5-Formylcytosine can be a stable DNA modification in mammals" (in en). Nature Chemical Biology 11 (8): 555–557. doi:10.1038/nchembio.1848. ISSN 1552-4469. PMID 26098680. 
  3. ↑ Ito, Shinsuke; Shen, Li; Dai, Qing; Wu, Susan C.; Collins, Leonard B.; Swenberg, James A.; He, Chuan; Zhang, Yi (2011-09-02). "Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine" (in en). Science 333 (6047): 1300–1303. doi:10.1126/science.1210597. ISSN 0036-8075. PMID 21778364. Bibcode: 2011Sci...333.1300I. 
  4. ↑ PubChem. "5-Formylcytosine" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/10986305. 
  5. ↑ Wu, Xiaoji; Zhang, Yi (2017). "TET-mediated active DNA demethylation: mechanism, function and beyond" (in en). Nature Reviews Genetics 18 (9): 517–534. doi:10.1038/nrg.2017.33. ISSN 1471-0064. PMID 28555658. https://www.nature.com/articles/nrg.2017.33. 
  6. ↑ Song, Chun-Xiao; Szulwach, Keith; Dai, Qing; Fu, Ye; Mao, Shi-Qing; Lin, Li; Street, Craig; Li, Yujing et al. (2013). "Genome-wide Profiling of 5-Formylcytosine Reveals Its Roles in Epigenetic Priming" (in en). Cell 153 (3): 678–691. doi:10.1016/j.cell.2013.04.001. PMID 23602153. 
  7. ↑ Wang, Yafen; Zhang, Xiong; Zou, Guangrong; Peng, Shuang; Liu, Chaoxing; Zhou, Xiang (2019-01-22). "Detection and Application of 5-Formylcytosine and 5-Formyluracil in DNA". Accounts of Chemical Research 52 (4): 1016–1024. doi:10.1021/acs.accounts.8b00543. ISSN 0001-4842. PMID 30666870. 
  8. ↑ Maiti, Atanu; Michelson, Anna Zhachkina; Armwood, Cherece J.; Lee, Jeehiun K.; Drohat, Alexander C. (2013-10-23). "Divergent Mechanisms for Enzymatic Excision of 5-Formylcytosine and 5-Carboxylcytosine from DNA". Journal of the American Chemical Society 135 (42): 15813–15822. doi:10.1021/ja406444x. ISSN 0002-7863. PMID 24063363. 
  9. ↑ Raiber, Eun-Ang; Murat, Pierre; Chirgadze, Dimitri Y.; Beraldi, Dario; Luisi, Ben F.; Balasubramanian, Shankar (2015). "5-Formylcytosine alters the structure of the DNA double helix" (in en). Nature Structural & Molecular Biology 22 (1): 44–49. doi:10.1038/nsmb.2936. ISSN 1545-9985. PMID 25504322. 
  10. ↑ Hardwick, Jack S; Ptchelkine, Denis; El-Sagheer, Afaf H; Tear, Ian; Singleton, Daniel; Phillips, Simon E V; Lane, Andrew N; Brown, Tom (2017). "5-Formylcytosine does not change the global structure of DNA" (in en). Nature Structural & Molecular Biology 24 (6): 544–552. doi:10.1038/nsmb.3411. ISSN 1545-9993. PMID 28504696. 
  11. ↑ Ngo, Thuy T. M.; Yoo, Jejoong; Dai, Qing; Zhang, Qiucen; He, Chuan; Aksimentiev, Aleksei; Ha, Taekjip (2016-02-24). "Effects of cytosine modifications on DNA flexibility and nucleosome mechanical stability" (in en). Nature Communications 7 (1): 10813. doi:10.1038/ncomms10813. ISSN 2041-1723. PMID 26905257. Bibcode: 2016NatCo...710813N. 
  12. ↑ Sanstead, Paul J.; Ashwood, Brennan; Dai, Qing; He, Chuan; Tokmakoff, Andrei (2020-02-20). "Oxidized Derivatives of 5-Methylcytosine Alter the Stability and Dehybridization Dynamics of Duplex DNA". The Journal of Physical Chemistry B 124 (7): 1160–1174. doi:10.1021/acs.jpcb.9b11511. ISSN 1520-6106. PMID 31986043. 
  13. ↑ Dubini, Romeo C. A.; Schön, Alexander; Müller, Markus; Carell, Thomas; Rovó, Petra (2020). "Impact of 5-formylcytosine on the melting kinetics of DNA by 1H NMR chemical exchange" (in en). Nucleic Acids Research 48 (15): 8796–8807. doi:10.1093/nar/gkaa589. PMID 32652019. 



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