AlkB Homologue 1 Demethylates N³-Methylcytidine in mRNA of Mammals.

RNA contains diverse modifications that exert important influences in a variety of cellular processes. So far more than 150 modifications have been identified in various RNA species, mainly in rRNA and tRNA. Recent research advances in RNA modifications have been sparked by the discovery of dynamic and reversible modifications in mRNA. Moving beyond the abundant tRNA and rRNA to mRNA is opening new directions in understanding RNA modification-mediated regulation of gene expression. Recently, it was reported that N³-methylcytidine (m³C) existed in mRNA of mammalian cells, and methyltransferase-like 8 (METTL8) was identified to be the writer enzyme of m³C. However, little is known about the eraser enzyme of m³C in mRNA. In the current study, we found that the AlkB homologue 1 (ALKBH1) was capable of demethylating m³C in mRNA of mammalian cells in vitro. Overexpression and knockdown of ALKBH1 in cultured human cells can induce decrease and increase of the level of m³C in mRNA, respectively, revealing the eraser enzyme property of ALKBH1 on m³C in mRNA. In addition, we observed significant decrease of the level of m³C in mRNA in hepatocellular carcinoma (HCC) tissues compared to tumor-adjacent normal tissues, which could be attributed to the increased expression of ALKBH1 as well as the decreased expression of METTL8 in HCC tissues. These results indicated that m³C in mRNA may play certain roles in tumorigenesis. Our study shed light on understanding the demethylation of m³C in mRNA.

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