Uncovering the assembly pathway of human ribosomes and its emerging links to disease

Abstract

The essential cellular process of ribosome biogenesis is at the nexus of various signalling pathways that coordinate protein synthesis with cellular growth and proliferation. The fact that numerous diseases are caused by defects in ribosome assembly underscores the importance of obtaining a detailed understanding of this pathway. Studies in yeast have provided a wealth of information about the fundamental principles of ribosome assembly, and although many features are conserved throughout eukaryotes, the larger size of human (pre‐)ribosomes, as well as the evolution of additional regulatory networks that can modulate ribosome assembly and function, have resulted in a more complex assembly pathway in humans. Notably, many ribosome biogenesis factors conserved from yeast appear to have subtly different or additional functions in humans. In addition, recent genome‐wide, RNAi‐based screens have identified a plethora of novel factors required for human ribosome biogenesis. In this review, we discuss key aspects of human ribosome production, highlighting differences to yeast, links to disease, as well as emerging concepts such as extra‐ribosomal functions of ribosomal proteins and ribosome heterogeneity.

Modification of Adenosine196 by Mettl3 Methyltransferase in the 5’-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation

“…We propose that the evolution of 47S pre-rRNA resulted in an additional quality control for initial stages of rRNA processing. This fact can be driven by the increased complexity of ribosome biogenesis in primates, including regulatory networks that modulate ribosome assembly and function [50], and high risks coming from dysregulation of this process. Qualitative changes in the nucleotide modifications during the ribosome assembly can also correlate with the proliferation of the cell and dictate its transformative potential.…”

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

“…In humans, this complex machinery comprises four ribosomal RNAs (the 28S, 18S, 5.8S and 5S rRNAs) that are synthesized by polymerases I and III, and 80 ribosomal proteins (RPs) transcribed by polymerase II [46], all of which are organized in a large 60S subunit and a small 40S subunit. From the transcription of the ribosomal DNA to the final export into the cytoplasm, ribosome biogenesis involves more than 400 proteins and small nucleolar RNAs (snoRNAs) [47]. Ribosome heterogeneity is the result of various changes including those in the diversity of the composition of RPs and RPs mutations, abnormalities in rRNA modifications during ribosomal biogenesis, and those due to specific endogenous or exogenous factors.…”

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

“…Ribosomal RNAs (rRNAs) represent~85% of the RNA mass in eukaryotic cells [6] and their biogenesis is finely regulated to guarantee a constant balance between their expression and that of the 80 ribosomal proteins (RPs) that ultimately constitute the ribosomes [55]. To facilitate such regulation, ribosomal biogenesis is temporally and spatially confined in the nucleolus, where one the two rRNA precursors, 47S, is transcribed by the RNA polymerase I and processed into the mature 18S of the 40S ribosomal subunit, and the 28S and 5.8S rRNAs of the 60S subunit [56].…”