5-Formylcytosine does not change the global structure of DNA

Hardwick, J.S.; Ptchelkine, Denis; El‐Sagheer, Afaf H.; Tear, Ian; Singleton, Daniel; Phillips, Simon E. V.; Lane, Andrew N.; Brown, Tom

doi:10.1038/nsmb.3411

Cited by 48 publications

(69 citation statements)

References 58 publications

(68 reference statements)

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“…The unmodified duplex (blue, PDB 5MVK) closely resembles its f C‐containing analog when crystallized under moderate salt conditions (magenta, PDB 5MVU). The same f C‐duplex, when crystallized in a buffer containing very high salt – 1.8 M lithium sulfate (green, PDB 4QKK), is also conformationally similar to the control, except at the unmodified ends, which are distorted due to crystal packing interactions . b) Overlays showing the base‐stacking between base pairs X4 · G′9 and G5 · X′8 of the structures featured in (a) showing that the base‐stacking geometry of f CpG steps is not unusual.…”

Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 71%

Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 96%

“…In contrast to the rotational dimorphism exhibited by the hydroxymethyl group of hm C, the formyl group of f C appears to be fixed in a single conformation in the plane of the cytosine ring facing toward the exocyclic N4‐amine, likely forming an intramolecular hydrogen bond (Figures b and 5a) . NMR‐based solution studies of f C‐modified DNA duplexes, and NMR and crystallographic studies of the free nucleoside have confirmed that this is the preferred conformation . Similarly, the carboxylate group of ca C also appears to form such an intramolecular hydrogen bond; crystal structures show that the carboxylate group of ca C is coplanar with the cytosine ring, and an NMR study suggests the intramolecular hydrogen bond may even be stronger than that of f C, presumably because the carboxyl group is negatively charged at physiological pH.…”

Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 97%

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Epigenetic Modifications of Cytosine: Biophysical Properties, Regulation, and Function in Mammalian DNA

2018

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To decode the function and molecular recognition of several recently discovered cytosine derivatives in the human genome - 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine - a detailed understanding of their effects on the structural, chemical, and biophysical properties of DNA is essential. Here, we review recent literature in this area, with particular emphasis on features that have been proposed to enable the specific recognition of modified cytosine bases by DNA-binding proteins. These include electronic factors, modulation of base-pair stability, flexibility, and radical changes in duplex conformation. We explore these proposals and assess whether or not they are supported by current biophysical data. This analysis is focused primarily on the properties of epigenetically modified DNA itself, which provides a basis for discussion of the mechanisms of recognition by different proteins.

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Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 71%

Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 96%

Section: Dna Containing Epigenetic Modifications: What Features Do Bimentioning

confidence: 97%

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Epigenetic Modifications of Cytosine: Biophysical Properties, Regulation, and Function in Mammalian DNA

2018

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“…In the case of densely fC‐modified DNA duplexes, conflicting results have been reported. In one study, significant fC‐induced changes of the duplex conformation were observed, whereas a second study reported crystal structures of fC‐modified duplexes with the same sequence (crystallized in a different space group) that exhibited only miminal changes in conformation compared to the corresponding unmodified duplexes (additional NMR studies supported the latter finding) . If dense modification of DNA with other oxidized mC derivatives can significantly affect DNA duplex conformations remains to be studied.…”

Section: Introductionmentioning

confidence: 99%

Recognition of Oxidized 5‐Methylcytosine Derivatives in DNA by Natural and Engineered Protein Scaffolds

Muñoz‐López

Summerer

2017

The Chemical Record

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Methylation of genomic cytosine to 5-methylcytosine is a central regulatory element of mammalian gene expression with important roles in development and disease. 5-methylcytosine can be actively reversed to cytosine via oxidation to 5-hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine by ten-eleven-translocation dioxygenases and subsequent base excision repair or replication-dependent dilution. Moreover, the oxidized 5-methylcytosine derivatives are potential epigenetic marks with unique biological roles. Key to a better understanding of these roles are insights into the interactions of the nucleobases with DNA-binding protein scaffolds: Natural scaffolds involved in transcription, 5-methylcytosine-reading and -editing as well as general chromatin organization can be selectively recruited or repulsed by oxidized 5-methylcytosines, forming the basis of their biological functions. Moreover, designer protein scaffolds engineered for the selective recognition of oxidized 5-methylcytosines are valuable tools to analyze their genomic levels and distribution. Here, we review recent structural and functional insights into the molecular recognition of oxidized 5-methylcytosine derivatives in DNA by selected protein scaffolds.

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“…[1][2][3][4][5][6][7] Biological effects of higher methylation levels at promoters are mediated by lowering the transcription of genes either by blocking the binding of transcription factors or by recruiting unique methyl-recognizing proteins that lower gene expression. Epigenetic modifications such as DNAmethylation play akey role in this endeavour.D NA methylation can be controlled by genetic means.Y et there are few chemical tools available for the spatial and temporal modulation of this modification.…”

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confidence: 99%

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

et al. 2019

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Controlling the functional dynamics of DNAwithin living cells is essential in biomedical research. Epigenetic modifications such as DNAmethylation play akey role in this endeavour.D NA methylation can be controlled by genetic means.Y et there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present as mall-molecule approach to modulate DNAm ethylation with light. The strategy uses aphoto-tuneable version of ac linically used drug (5-aza-2'-deoxycytidine) to alter the catalytic activity of DNAmethyltransferases,the enzymes that methylate DNA. After uptake by cells,t he photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells.T he chemical tool complements genetic,b iochemical, and pharmacological approaches to study the role of DNAm ethylation in biology and medicine.The methylation of DNAatposition 5ofcytosine residues is chemically av ery simple but biologically one of the most important modifications of DNA. It influences many biological processes in humans such as the regulation of cell function, cellular reprogramming,a nd organismal development. [1][2][3][4][5][6][7] Biological effects of higher methylation levels at promoters are mediated by lowering the transcription of genes either by blocking the binding of transcription factors or by recruiting unique methyl-recognizing proteins that lower gene expression. Altered levels of methylation are also associated with several diseases [8][9][10][11] including cancer. [8,[12][13][14][15][16] Driven by the growing importance of DNAmethylation in biomedical research, there is as trong interest to experimentally lower or increase methylation levels [17][18][19][20][21][22][23] to study,f or example,t he role of epigenetic reprogramming in tissue development or regenerative medicine. [24,25] Optical control is of particular relevance given the high spatial and temporal resolution of light. Often, the approach is implemented with photosensitive small molecules of tuneable bioactivity. [26][27][28][29][30][31] These can be used without the need for genetic engineering of cells leading to powerful applications within cell biology. [32] Yet, despite the importance of DNAm ethylation in biology, no light-tuneable small-molecule tool has been developed to manipulate methylation levels in cells.Herein, we present ap hoto-mediated small-molecule strategy that modulates methylation in light-exposed cells. At the approachsc entre is an inhibitor that interferes with DNAmethyltransferases (DNMTs), the enzymes responsible for DNAm ethylation [33] including the maintenance DNA methyltransferase 1( DNMT1). [34] Thei nhibitorsb ioactivity becomes tuneable with light by the chemical derivatization with ap hotocage.A ss chematically illustrated in Figure 1a, the attached photocage renders the inhibitor biologically inactive.However, light exposure cleaves off the photocage to restore the original inhibitory effect (Figure 1a). Thep hotocaged molecule is hence expected...

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5-Formylcytosine does not change the global structure of DNA

Cited by 48 publications

References 58 publications

Epigenetic Modifications of Cytosine: Biophysical Properties, Regulation, and Function in Mammalian DNA

Epigenetic Modifications of Cytosine: Biophysical Properties, Regulation, and Function in Mammalian DNA

Recognition of Oxidized 5‐Methylcytosine Derivatives in DNA by Natural and Engineered Protein Scaffolds

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

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