N6-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation

N-6-Methyladenosine (m(6)A) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA m(6)A modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of m(6)A methyltransferases for rRNAs and the function of rRNA m(6)A modifications are unknown. Here we report a new m(6)A methyltransferase, ZCCHC4, which primarily methylates human 28S rRNA and also interacts with a subset of mRNAs. ZCCHC4 knockout eliminates m 6 A4220 modification in 28S rRNA, reduces global translation, and inhibits cell proliferation. We also find that ZCCHC4 protein is overexpressed in hepatocellular carcinoma tumors, and ZCCHC4 knockout significantly reduces tumor size in a xenograft mouse model. Our results highlight the functional significance of an rRNA m(6)A modification in translation and in tumor biology.