In a paper published in Nature on May 2, a research team led by Dr. XU Guoliang from the Shanghai Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences (CAS), Dr. TANG Huiru from Fudan University, and Dr. HUANG Kaiyao from the Institute of Hydrobiology of CAS, discovered a novel vitamin-C-derived DNA modification in green alga Chlamydomonas reinhardtii.
This modification is catalyzed by a ten-eleven translocation (TET) homologue, of which the catalytic mechanism and physiological function were also elucidated.
5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. It is iteratively oxidized by TET proteins to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which promotes DNA demethylation in mammalian cells.
TET homologues also present in a wide variety of other eukaryotes. However, their enzymatic activities and physiological functions remain elusive.
Researchers firstly identified eight TET homologues by searching TET/JBP domain containing proteins in C. reinhardtii. Using 5mC-containing DNA as the substrate, one of the homologues, namely CrTET1 or CMD1, is able to convert 5mC into two unidentified products.
Nuclear magnetic resonance (NMR) analysis showed that both products contain a glyceryl moiety at the methyl carbon of 5mC. These two stereoisomers are thus identified as 5-glyceryl-methylcytosine (5gmC).
In search of the origin of the glyceryl moiety, researchers found that 2-oxoglutarate, the co-substrate for the conventional dioxygenases, is dispensable for CMD1-catalysed reaction. Surprisingly, vitamin C (VC) is an essential co-factor for CMD1 catalysis. In the reaction, the glyceryl portion of VC is transferred to 5mC to generate 5gmC in DNA, releasing CO2 and glyoxylic acid as by-products.
The VC-derived DNA modification is present in the genome of C. reinhardtii, and its level decreases significantly in a CMD1 mutant strain generated by a CRISPR/Cas9-based co-selection strategy.
Moreover, the tolerance towards high light exposure of CMD1 mutant cells is compromised compared to wild-type strains. In the absence of CMD1, LHCSR3, a critical gene for protecting C. reinhardtii from photooxidative damage, is hypermethylated and downregulated compared to wild-type cells, leading to a reduced photoprotective capacity of non-photochemical quenching, which is known to contribute to dissipate excess light energy to heat in plants.
Overall, this study uncovered a novel type of eukaryotic DNA base modification, which is generated by a divergent TET homologue and unexpectedly derived from vitamin C. This modification may counteract DNA methylation and epigenetically regulate vital physiologic processes or stress responses.
The findings highlight the structural versatility of DNA in association of organismal environmental adaptation, and uncover a hitherto unappreciated contribution of vitamin C in the catalytic reaction in biochemistry.
Scientists at the University of Chicago, Harvard University and the Chinese Academy of Sciences have described the surprising discovery and function of a new DNA modification in insects, worms and algae. Common DNA modifications occur through methylation, a chemical process that can dramatically change gene expression, which regulates the eventual production of proteins that carry out the functions of an organism. It’s all part of a growing new subfield of epigenetics being pioneered by Professor Chuan He and his collaborators.
Researchers from Institute of Hydrobiology, Shanghai Institute of Biochemistry and Cell Biology, and Fudan University uncovered that in unicellular green algae Chlamydomonas reinhardtii how the ten-eleven translocation family protein promote modification of the methyl group in 5mC.
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