The emerging importance of METTL5-mediated ribosomal RNA methylation

Brain development: the role of ribosomal RNA modification A specific modification of ribosomal RNA (rRNA) may contribute to intellectual disability and cognitive dysfunction. All RNA molecules, including rRNA, are biochemically modified after transcription. Modifications can be influenced by external factors and can affect gene expression, although the exact mechanisms remain unclear. Elena Turkalj and Caroline Vissers at the University of California San Francisco, USA, reviewed current understanding of an rRNA modification called m(6)A(1832) carried out by METTL5, a methyltransferase enzyme that plays a significant role in early development. Recent studies suggest that methylation of rRNA, including the m(6)A(1832) modification, directly influences brain development and cognition. METTL5 gene mutations are linked with intellectual disabilities. Future work should examine how m(6)A(1832) modifications vary under different biological and environmental conditions, and how they are linked to METTL5 expression. The study of the epitranscriptome has thus far focused largely on mRNA methylation. Recent human genetics studies suggest that methylation of ribosomal RNA also contributes to brain development and cognition. In particular, the m(6)A modification at the A-1832 position of the 18S rRNA is installed by METTL5. Mutations or deletions of Mettl5 in humans and mice, respectively, cause abnormal translation and gene expression that in turn mediates stem cell behaviors such as differentiation. In this review, we provide an overview of the current knowledge of the methyltransferase METTL5, as well as the molecular biology surrounding m(6)A on rRNA and how it regulates cell behavior.