5-Formylcytosine
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| ImageFile = 5-Formylcytosine.svg
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| ImageSize = 150px
| ImageAlt = Skeletal formula of 5-formylcytosine
| ImageSize1 = 170
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| PIN = 4-Amino-2-oxo-1,2-dihydropyrimidine-5-carbaldehyde
| Section1 = {{Chembox Identifiers
| CASNo=4425-59-6
| ChEBI = 76794
| ChemSpiderID = 9161502
| PubChem=10986305
| StdInChI=1S/C5H5N3O2/c6-4-3(2-9)1-7-5(10)8-4/h1-2H,(H3,6,7,8,10)
| StdInChIKey = FHSISDGOVSHJRW-UHFFFAOYSA-N
| SMILES = C1=NC(=O)NC(=C1C=O)N
}}
| Section2 = {{Chembox Properties
| C = 5 | H = 5 | N = 3 | O = 2
| Appearance = Yellow solid
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| Section3 = {{Chembox Hazards
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| verifiedrevid = 477224648
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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{{Cite journal|last1=Pfaffeneder|first1=Toni|last2=Hackner|first2=Benjamin|last3=Truß|first3=Matthias|last4=Münzel|first4=Martin|last5=Müller|first5=Markus|last6=Deiml|first6=Christian A.|last7=Hagemeier|first7=Christian|last8=Carell|first8=Thomas|date=2011|title=The Discovery of 5-Formylcytosine in Embryonic Stem Cell DNA|journal=Angewandte Chemie International Edition|volume=50|issue=31|pages=7008–7012|doi=10.1002/anie.201103899|pmid=21721093|issn=1521-3773}} 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.{{Cite journal|last1=Bachman|first1=Martin|last2=Uribe-Lewis|first2=Santiago|last3=Yang|first3=Xiaoping|last4=Burgess|first4=Heather E.|last5=Iurlaro|first5=Mario|last6=Reik|first6=Wolf|last7=Murrell|first7=Adele|last8=Balasubramanian|first8=Shankar|date=2015|title=5-Formylcytosine can be a stable DNA modification in mammals|journal=Nature Chemical Biology|language=en|volume=11|issue=8|pages=555–557|doi=10.1038/nchembio.1848|pmid=26098680|pmc=5486442|issn=1552-4469}} In mammals, 5fC is formed by oxidation of 5-hydroxymethylcytosine (5hmC) a reaction mediated by TET enzymes.{{Cite journal|last1=Ito|first1=Shinsuke|last2=Shen|first2=Li|last3=Dai|first3=Qing|last4=Wu|first4=Susan C.|last5=Collins|first5=Leonard B.|last6=Swenberg|first6=James A.|last7=He|first7=Chuan|last8=Zhang|first8=Yi|date=2011-09-02|title=Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine|journal=Science|language=en|volume=333|issue=6047|pages=1300–1303|doi=10.1126/science.1210597|issn=0036-8075|pmc=3495246|pmid=21778364|bibcode=2011Sci...333.1300I}} Its molecular formula is C5H5N3O2.{{Cite web|last=PubChem|title=5-Formylcytosine|url=https://pubchem.ncbi.nlm.nih.gov/compound/10986305|access-date=2020-07-26|website=pubchem.ncbi.nlm.nih.gov|language=en}}
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.{{Cite journal|last1=Wu|first1=Xiaoji|last2=Zhang|first2=Yi|date=2017|title=TET-mediated active DNA demethylation: mechanism, function and beyond|url=https://www.nature.com/articles/nrg.2017.33|journal=Nature Reviews Genetics|language=en|volume=18|issue=9|pages=517–534|doi=10.1038/nrg.2017.33|pmid=28555658|s2cid=3393814|issn=1471-0064|url-access=subscription}} The specific concentration values vary significantly depending on the cell type.{{Cite journal|last1=Song|first1=Chun-Xiao|last2=Szulwach|first2=Keith|last3=Dai|first3=Qing|last4=Fu|first4=Ye|last5=Mao|first5=Shi-Qing|last6=Lin|first6=Li|last7=Street|first7=Craig|last8=Li|first8=Yujing|last9=Poidevin|first9=Mickael|last10=Wu|first10=Hao|last11=Gao|first11=Juan|date=2013|title=Genome-wide Profiling of 5-Formylcytosine Reveals Its Roles in Epigenetic Priming|journal=Cell|language=en|volume=153|issue=3|pages=678–691|doi=10.1016/j.cell.2013.04.001|pmc=3657391|pmid=23602153}} 5fC can be aberrantly expressed in distinct sets of tissue that can indicate different tumor onsets and canceration.{{Cite journal|last1=Wang|first1=Yafen|last2=Zhang|first2=Xiong|last3=Zou|first3=Guangrong|last4=Peng|first4=Shuang|last5=Liu|first5=Chaoxing|last6=Zhou|first6=Xiang|date=2019-01-22|title=Detection and Application of 5-Formylcytosine and 5-Formyluracil in DNA|journal=Accounts of Chemical Research|volume=52|issue=4|pages=1016–1024|doi=10.1021/acs.accounts.8b00543|pmid=30666870|s2cid=58623597 |issn=0001-4842}}
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.{{Cite journal|last1=Maiti|first1=Atanu|last2=Michelson|first2=Anna Zhachkina|last3=Armwood|first3=Cherece J.|last4=Lee|first4=Jeehiun K.|last5=Drohat|first5=Alexander C.|date=2013-10-23|title=Divergent Mechanisms for Enzymatic Excision of 5-Formylcytosine and 5-Carboxylcytosine from DNA|journal=Journal of the American Chemical Society|volume=135|issue=42|pages=15813–15822|doi=10.1021/ja406444x|issn=0002-7863|pmc=3930231|pmid=24063363}} Secondly, 5fC can exist as an independent, stable modification, but its role in this context is still blurry.
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.{{Cite journal|last1=Raiber|first1=Eun-Ang|last2=Murat|first2=Pierre|last3=Chirgadze|first3=Dimitri Y.|last4=Beraldi|first4=Dario|last5=Luisi|first5=Ben F.|last6=Balasubramanian|first6=Shankar|date=2015|title=5-Formylcytosine alters the structure of the DNA double helix|url= |journal=Nature Structural & Molecular Biology|language=en|volume=22|issue=1|pages=44–49|doi=10.1038/nsmb.2936|pmid=25504322|s2cid=10288745|issn=1545-9985|pmc=4287393}}{{Cite journal|last1=Hardwick|first1=Jack S|last2=Ptchelkine|first2=Denis|last3=El-Sagheer|first3=Afaf H|last4=Tear|first4=Ian|last5=Singleton|first5=Daniel|last6=Phillips|first6=Simon E V|last7=Lane|first7=Andrew N|last8=Brown|first8=Tom|date=2017|title=5-Formylcytosine does not change the global structure of DNA|journal=Nature Structural & Molecular Biology|language=en|volume=24|issue=6|pages=544–552|doi=10.1038/nsmb.3411|issn=1545-9993|pmc=5747368|pmid=28504696}} On the other hand, several researchers working independently have identified 5fC to distinctly increase DNA flexibility.{{Cite journal|last1=Ngo|first1=Thuy T. M.|last2=Yoo|first2=Jejoong|last3=Dai|first3=Qing|last4=Zhang|first4=Qiucen|last5=He|first5=Chuan|last6=Aksimentiev|first6=Aleksei|last7=Ha|first7=Taekjip|author7-link=Taekjip Ha|date=2016-02-24|title=Effects of cytosine modifications on DNA flexibility and nucleosome mechanical stability|journal=Nature Communications|language=en|volume=7|issue=1|page=10813|doi=10.1038/ncomms10813|pmid=26905257|pmc=4770088|bibcode=2016NatCo...710813N|issn=2041-1723}}{{Cite journal|last1=Sanstead|first1=Paul J.|last2=Ashwood|first2=Brennan|last3=Dai|first3=Qing|last4=He|first4=Chuan|last5=Tokmakoff|first5=Andrei|date=2020-02-20|title=Oxidized Derivatives of 5-Methylcytosine Alter the Stability and Dehybridization Dynamics of Duplex DNA|journal=The Journal of Physical Chemistry B|volume=124|issue=7|pages=1160–1174|doi=10.1021/acs.jpcb.9b11511|issn=1520-6106|pmc=7136776|pmid=31986043}} 5fC also curtails DNA double helix stability and increases base pair opening.{{Cite journal|last1=Dubini|first1=Romeo C. A.|last2=Schön|first2=Alexander|last3=Müller|first3=Markus|last4=Carell|first4=Thomas|last5=Rovó|first5=Petra|title=Impact of 5-formylcytosine on the melting kinetics of DNA by 1H NMR chemical exchange|journal=Nucleic Acids Research|year=2020|volume=48|issue=15|pages=8796–8807|language=en|doi=10.1093/nar/gkaa589|pmid=32652019|pmc=7470965|doi-access=free}}