Identification of the m6Am Methyltransferase PCIF1 Reveals the Location and Functions of m6Am in the Transcriptome.

During stress, while global mRNA translation is reduced, specific stress-responsive transcripts are translated. How stress-responsive mRNAs are selectively translated is unknown. Ribosome modifications may facilitate selective translation of specific transcripts in different cell types under differing conditions. Here we identify METL-5 as a C. elegans N6-adenosine methyltransferase that methylates adenosine 1717 on 18S rRNA. METL-5 specifically enhances ribosomal binding and selective translation of a cytochrome P450 mRNA, cyp-29A3, whose protein product oxidizes the omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid to eicosanoids, important signaling molecules in stress responses. In fact although mutant metl-5 C. elegans grow normally under homeostatic conditions, they are resistant to a variety of stresses, including heat shock, cold, oxidants and UV irradiation. metl-5 mutant worms have reduced overall lipid levels and of bioactive lipid eicosanoids. Moreover, dietary supplementation of eicosanoid products of CYP-29A3 restores stress sensitivity of metl-5 mutant worms. Thus methylation of a specific residue of 18S rRNA by METL-5 selectively enhances translation of cyp-29A3, to increase production of eicosanoids that increase stress-related death. Overall design: Comparing transcriptomes and ribosome profiles of adult nematode worms. Two strains (WT and DMETL-5), two temperatures (20 and 37 °C), 3 replicates in each group.