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A vitamin-C-derived DNA modification catalysed by an algal TET homologue

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Chlamydomonas reinhardtii

PROVIDER: GSE122719 | GEO | 2019/05/01

REPOSITORIES: GEO

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A vitamin-C-derived DNA modification catalysed by an algal TET homologue.

Project description:Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals1,2. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases3. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate4, CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.

| S-EPMC6628258 | biostudies-literature

Molecular mechanism for vitamin C-derived C<sup>5</sup>-glyceryl-methylcytosine DNA modification catalyzed by algal TET homologue CMD1.

Project description:C5-glyceryl-methylcytosine (5gmC) is a novel DNA modification catalyzed by algal TET homologue CMD1 using vitamin C (VC) as co-substrate. Here, we report the structures of CMD1 in apo form and in complexes with VC or/and dsDNA. CMD1 exhibits comparable binding affinities for DNAs of different lengths, structures, and 5mC levels, and displays a moderate substrate preference for 5mCpG-containing DNA. CMD1 adopts the typical DSBH fold of Fe2+/2-OG-dependent dioxygenases. The lactone form of VC binds to the active site and mono-coordinates the Fe2+ in a manner different from 2-OG. The dsDNA binds to a positively charged cleft of CMD1 and the 5mC/C is inserted into the active site and recognized by CMD1 in a similar manner as the TET proteins. The functions of key residues are validated by mutagenesis and activity assay. Our structural and biochemical data together reveal the molecular mechanism for the VC-derived 5gmC DNA modification by CMD1.

| S-EPMC7854593 | biostudies-literature

A vitamin-C-derived DNA modification catalysed by an algal TET homologue

Project description:A vitamin-C-derived DNA modification catalysed by an algal TET homologue

| PRJNA506063 | ENA

Vitamin C induces Tet-dependent DNA demethylation in ES cells to promote a blastocyst-like methylome

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-30 | E-GEOD-46403 | biostudies-arrayexpress

Novel DNA modification in mouse ESC

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-03-30 | E-GEOD-71866 | biostudies-arrayexpress

Vitamin C induces Tet-dependent DNA demethylation in ES cells to promote a blastocyst-like methylome

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-06-30 | GSE46403 | GEO

Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-07-16 | E-GEOD-67351 | biostudies-arrayexpress

The role of Vitamin C and TET dioxygenases in genome-wide features of regulatory T cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-19 | GSE141152 | GEO

The human AlkB homologue 4 interacts with proteins associated with transcription

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-01 | E-GEOD-39135 | biostudies-arrayexpress

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-23 | GSE225980 | GEO

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