The Ptch methylase installs an m3U modification on 28S rRNA for efficient protein synthesis in flies and men

Abstract

The ribosomal RNA (rRNA) is one of the most heavily modified RNA species in nature. Although we have advanced knowledge of the sites, functions and the enzymology of many of the rRNA modifications from all kingdoms, we lack basic understanding on many of those that are not universally present. A single N3 modified Uridine base (m3U) was identified on the 28S rRNA from human and frog over thirty years ago, which is absent in bacteria or yeast. Here we show that the equivalent m3U is present in Drosophila, and that the Ptch enzyme and its human homolog are both necessary and sufficient for carrying out the modification. The Ptch-modified U is at a functional center of the large ribosome, and consistently ptch-mutant cells suffer loss of ribosomal functions. Ptch, proposed to be the most druggable RNA methyltransferases in human, represents a unique target where ribosomal functions could be specifically compromised in cancer cells.