The mysterious presence of a 5-methylcytosine oxidase in the<i>Drosophila</i>genome

Dunwell, Thomas L.; McGuffin, Liam J.; Dunwell, Jim M.; Pfeifer, Gerd P.

doi:10.4161/cc.26540

Cited by 35 publications

(40 citation statements)

References 78 publications

(88 reference statements)

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“…S3, A and B). Drosophila possesses only one conserved Tet ortholog, CG43444 (dTet) (10,11). Depletion of dTet in S2 cells, by using RNA interference for dTet (dTet KD), revealed a 54% decrease in dTet transcripts, as compared with control cells (Fig.…”

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confidence: 99%

Transcriptome-wide distribution and function of RNA hydroxymethylcytosine

Delatte

Wang

Ngoc

et al. 2016

Science

358

396

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#Hydroxymethylcytosine, well described in DNA, occurs also in RNA. Here, we show that hydroxymethylcytosine preferentially marks polyadenylated RNAs and is deposited by Tet in Drosophila. We map the transcriptome-wide hydroxymethylation landscape, revealing hydroxymethylcytosine in the transcripts of many genes, notably in coding sequences, and identify consensus sites for hydroxymethylation. We found that RNA hydroxymethylation can favor mRNA translation. Tet and hydroxymethylated RNA are found to be most abundant in the Drosophila brain, and Tet-deficient fruitflies suffer impaired brain development, accompanied by decreased RNA hydroxymethylation. This study highlights the distribution, localization, and function of cytosine hydroxymethylation and identifies central roles for this modification in Drosophila.

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confidence: 99%

Transcriptome-wide distribution and function of RNA hydroxymethylcytosine

Delatte

Wang

Ngoc

et al. 2016

Science

358

396

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“…theless, the Drosophila genome harbors a well conserved homolog of the mammalian Tet gene, the function of which is currently unknown (40). It is possible that Drosophila Tet may oxidize other methylated bases, such as thymine in DNA or 5mC in tRNA (generated by Dnmt2 (41)) or N6mA in mRNA or DNA.…”

Section: Tet Proteins Are 5-methylpyrimidine Dioxygenases But Not Dementioning

confidence: 99%

The Mechanisms of Generation, Recognition, and Erasure of DNA 5-Methylcytosine and Thymine Oxidations

Hashimoto

Zhang

Vertino

et al. 2015

Journal of Biological Chemistry

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One of the most fundamental questions in the control of gene expression in mammals is how the patterns of epigenetic modifications of DNA are generated, recognized, and erased. This includes covalent cytosine methylation of DNA and its associated oxidation states. An array of AdoMet-dependent methyltransferases, Fe(II)-and ␣-ketoglutarate-dependent dioxygenases, base excision glycosylases, and sequence-specific transcription factors is responsible for changing, maintaining, and interpreting the modification status of specific regions of chromatin. This review focuses on recent developments in characterizing the functional and structural links between the modification status of two DNA bases 5-methylcytosine and thymine (5-methyluracil).In the DNA of higher organisms, cytosine exists in several chemical forms, including unmodified cytosine (C), 5-methylcytosine (5mC), 2 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (1-5). These forms are genetically equivalent in terms of base-pairing and protein-coding, but differ in how they interact with macromolecules and influence gene expression. There is much interest in the effects of these modifications in epigenetic regulation, in development and differentiation, in neuron function, and in diseases. In general, the modifications (or "marks") are added to cytosine in situ, following its incorporation into DNA in the unmodified form. DNA methyltransferases (Dnmt) convert certain cytosines to 5mC, usually within the sequence context CpG (6, 7) or CpA (8). A subset of these 5mC residues is then converted to 5hmC, 5fC, and 5caC in consecutive Fe(II)-and ␣-ketoglutarate-dependent oxidation reactions by the teneleven translocation (Tet) dioxygenases (2-4). The Tet dioxygenases are widely distributed across the eukaryotic tree of life, from mammals to the amoeboflagellate Naegleria gruberi (9), mushroom (Coprinopsis cinerea) (10), and honey bee (Apis mellifera) (11). High-throughput methods for characterizing 5mC oxidation states at single base resolution are becoming available, so our understanding of 5mC oxidation is expected to develop rapidly. In this minireview, we focus on the mechanisms of generating, recognizing, and possibly erasing 5mC and its oxidative forms in DNA. Tet Proteins Are 5-Methylpyrimidine Dioxygenases, but Not Demethylating EnzymesChromatin regulates transcriptional processes through postsynthetic modifications of both of its components: DNA and histones (Fig. 1a). Much remains to be learned about how the combination of these modifications (or lack thereof) facilitates or silences transcription. One broad theme has emerged that a web of interactions tightly coordinates the modification of a segment of DNA and its associated histones, affecting local chromatin structure and determining the functional states. The Tet enzymes belong to a family of Fe(II)-and ␣-ketoglutaratedependent dioxygenases that also includes the Jumonji domain-containing histone lysine demethylases, the N-methyl nucleic acid demethylase includin...

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“…There is one other potential exception, the model dipteran species Drosophila melanogaster . The presence of 5mC in the Drosophila genome has been subject to long standing debates from as early as the 1980s with frequent conflicting reports claiming either proof for, or against, the presence of 5mC (1). …”

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confidence: 99%

“…The genome of D. melanogaster , as well as seemingly the whole order of Diptera , varies significantly from that of humans, honeybees and other insects, in that it only contains a single recognised DNMT ortholog of DMNT2 (Mt2) which means there is no apparent method for establishing de novo 5mC marks. D. melanogaster also has a single ortholog of the TET family proteins which in humans are known to use 5mC as a substrate (1). These are somewhat conflicting ideas, an enzyme that uses 5mC as a substrate, but no enzyme to make that substrate?…”

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confidence: 99%

“…We recently presented evidence for the presence of 5mC in Drosophila based on the occurrence of dTet, a well-conserved member of the TET 5mC dioxygenases family in Drosophila (1). The strength of evidence for the presence of 5mC discussed above now seems to outweigh the evidence for absence and the recent findings now immediately suggests the logical presence of dTet in the fly genome.…”

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