Nucleic acid dioxygenase ALKBH1
oxidative RNA demethylase activity
AlkB Homologue 1 Demethylates <i>N</i><sup>3</sup>-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 <i>N</i><sup>3</sup>-methylcytidine (m<sup>3</sup>C) existed in mRNA of mammalian cells, and methyltransferase-like 8 (METTL8) was identified to be the writer enzyme of m<sup>3</sup>C. However, little is known about the eraser enzyme of m<sup>3</sup>C in mRNA. In the current study, we found that the AlkB homologue 1 (ALKBH1) was capable of demethylating m<sup>3</sup>C in mRNA of mammalian cells <i>in vitro</i>. Overexpression and knockdown of ALKBH1 in cultured human cells can induce decrease and increase of the level of m<sup>3</sup>C in mRNA, respectively, revealing the eraser enzyme property of ALKBH1 on m<sup>3</sup>C in mRNA. In addition, we observed significant decrease of the level of m<sup>3</sup>C in mRNA in hepatocellular carcinoma (HCC) tissues compared to tumor-adjacent normal tissues, which could be attributed to the increased expression of <i>ALKBH1</i> as well as the decreased expression of <i>METTL8</i> in HCC tissues. These results indicated that m<sup>3</sup>C in mRNA may play certain roles in tumorigenesis. Our study shed light on understanding the demethylation of m<sup>3</sup>C in mRNA.