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Reversal of nucleobase methylation by dioxygenases

Abstract

The repertoire of nucleobase methylation in DNA and RNA, introduced by chemical agents or enzymes, is large. Most methylation can be reversed either directly by restoration of the original nucleobase or indirectly by replacement of the methylated nucleobase with an unmodified nucleobase. In many direct and indirect demethylation reactions, ALKBH (AlkB homolog) and TET (ten eleven translocation) hydroxylases play a role. Here, we suggest a chemical classification of methylation types. We then discuss pathways for removal, emphasizing oxidation reactions. We highlight the recently expanded repertoire of ALKBH- and TET-catalyzed reactions and describe the discovery of a TET-like protein that resembles the hydroxylases but uses an alternative co-factor and catalyzes glyceryl transfer rather than hydroxylation.

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Fig. 1: Classification of enzymatically and chemically methylated nucleobases, ordered according to methylation type.
Fig. 2: Ease of chemical methylation and biochemical properties of methylated nucleobases.
Fig. 3: Occurrence and biological role of enzymatically catalyzed RNA and DNA methylation.
Fig. 4: Nucleobase demethylation pathways with representative substrates.
Fig. 5: Pathways for reversal of methylation.
Fig. 6: Key steps in hydroxylation by ALKBH or TET dioxygenases.
Fig. 7: Comparison of ALKBH (green, left) and TET (green, right) active sites.
Fig. 8: Mechanism of glycerination of 5mC by CMD1.

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Acknowledgements

G.X.’s work is supported by the National Key R&D Program of China (2018YFA0800303, 2017YFA0102700), the National Science Foundation of China (31430049, 31830018, 31991163), the Chinese Academy of Sciences (XDB19010102), and CAMS Innovation Fund for Medical Sciences (CIFMS-2019-I2M-5-077). M.B.’s work is supported by grants from the Polish National Science Centre (NCN, 2014/13/B/NZ1/03991, 2014/14/M/NZ5/00558, 2017/27/L/NZ2/03234, 2018/30/Q/NZ2/00669), the Foundation for Polish Science (FNP, POIR.04.04.00-00-5D81/17-00), and the Polish National Agency for Academic Exchange (NAWA, PPI/APM/2018/1/00034). We thank J. Gui, C. Yang, C. Yi and A. Slyvka for insightful discussions, and lab members and A. Xu for proofreading the final text.

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Xu, GL., Bochtler, M. Reversal of nucleobase methylation by dioxygenases. Nat Chem Biol 16, 1160–1169 (2020). https://doi.org/10.1038/s41589-020-00675-5

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