Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function

Abstract

rRNAs are extensively modified during their transcription and subsequent maturation in the nucleolus, nucleus and cytoplasm. RNA modifications, which are installed either by snoRNA-guided or by stand-alone enzymes, generally stabilize the structure of the ribosome. However, they also cluster at functionally important sites of the ribosome, such as the peptidyltransferase center and the decoding site, where they facilitate efficient and accurate protein synthesis. The recent identification of sites of substoichiometric 2'-O-methylation and pseudouridylation has overturned the notion that all rRNA modifications are constitutively present on ribosomes, highlighting nucleotide modifications as an important source of ribosomal heterogeneity. While the mechanisms regulating partial modification and the functions of specialized ribosomes are largely unknown, changes in the rRNA modification pattern have been observed in response to environmental changes, during development, and in disease. This suggests that rRNA modifications may contribute to the translational control of gene expression.

Keywords: RNA methyltransferase; RNA modification; acetylation; methylation; pseudouridylation; ribosome; ribosomopathy; snoRNA; translation.

Figure 1.

Structures of box C/D and box H/ACA sRNP complexes. (A) Structural model of an H/ACA box sRNP from Pyrococcus furiosus (PDB 3HAY) A surface view of the protein components is shown and sRNA and rRNA are indicated in dark gray and red, respectively. (B) Structural model of a Sulfolobus solfataricus box C/D sRNP (PDB 3PLA) is shown as in A. The modified nucleotide is shown in surface view. Note, that archaeal L7Ae is an ortholog of eukaryotic Snu13 and in eukaryotes, Nop56 and Nop58 are orthologous to archaeal Nop5.

Figure 2.

Base modifications in rRNA and the enzymes that install them. (A) Chemical structures of the 4 nucleotides and the modifications that are added in yeast rRNAs. The additional chemical groups are marked in red and the enzymes that introduce them in yeast are indicated above the arrow (yellow) and in humans below the arrow (green). (B) Three-step modification pathway for U1191 of the 18S rRNA in yeast.

Figure 3.

Distribution of rRNA modifications on the yeast ribosome. The S. cerevisiae 80S ribosome (PBD 4V88) is shown – 40S in teal and 60S in gray. The positions of 2′-O-methylations (purple), pseudouridines (blue) and base modification installed by stand-alone enzymes (orange) are indicated. Three functionally important regions of the ribosome, the peptidyltransferase center (PTC), the decoding site and the intersubunit bridge eB14, are also shown in a magnified view.