Claudia Schneider

Ribosome biogenesis is one of the biggest consumers of cellular energy. More than 20 genetic diseases (ribosomopathies) and multiple cancers arise from defects in the production of the 40S (SSU) and 60S (LSU) ribosomal subunits. Defects in the production of either the SSU or LSU result in p53 induction through the accumulation of the 5S RNP, an LSU assembly intermediate. While the mechanism is understood for the LSU, it is still unclear how SSU production defects induce p53 through the 5S RNP since the production of the two subunits is believed to be uncoupled. Here, we examined the response to SSU production defects to understand how this leads to the activation of p53 via the 5S RNP. We found that p53 activation occurs rapidly after SSU production is blocked, prior to changes in mature ribosomal RNA (rRNA) levels but correlated with early, middle and late SSU pre-rRNA processing defects. Furthermore, both nucleolar/nuclear LSU maturation, in particular late stages in 5.8S rRNA processing, and pre-LSU export were affected by SSU production defects. We have therefore uncovered a novel connection between the SSU and LSU production pathways in human cells, which explains how p53 is induced in response to SSU production defects.

Ribosomes are essential macromolecular machines responsible for translating the genetic information encoded in mRNAs into proteins. Ribosomes are composed of ribosomal RNAs and proteins (rRNAs and RPs) and the rRNAs fulfill both catalytic and architectural functions. Excision of the mature eukaryotic rRNAs from their precursor transcript is achieved through a complex series of endoribonucleolytic cleavages and exoribonucleolytic processing steps that are precisely coordinated with other aspects of ribosome assembly. Many ribonucleases involved in pre‐rRNA processing have been identified and pre‐rRNA processing pathways are relatively well defined. However, momentous advances in cryo‐electron microscopy have recently enabled structural snapshots of various pre‐ribosomal particles from budding yeast ( Saccharomyces cerevisiae ) and human cells to be captured and, excitingly, these structures not only allow pre‐rRNAs to be observed before and after cleavage events, but also enable ribonucleases to be visualized on their target RNAs. These structural views of pre‐rRNA processing in action allow a new layer of understanding of rRNA maturation and how it is coordinated with other aspects of ribosome assembly. They illuminate mechanisms of target recognition by the diverse ribonucleases involved and reveal how the cleavage/processing activities of these enzymes are regulated. In this review, we discuss the new insights into pre‐rRNA processing gained by structural analyses and the growing understanding of the mechanisms of ribonuclease regulation. This article is categorized under: Translation > Ribosome Biogenesis RNA Processing > rRNA Processing