Impaired assembly of cells' protein-synthesis factories, the ribosomes, can cause cell-cycle arrest and disease. This finding emphasizes the close link between cell proliferation and ribosome formation.
Protein synthesis is mediated by complexes of RNA and protein known as ribosomes. Ribosome biogenesis is complicated, involving some 150 non-ribosomal factors and 100 small non-coding RNAs1,2. It is also the most energy-consuming process in growing cells, and so requires extensive regulation and coordination. Pressing questions are how ribosome synthesis is regulated, how it links to cell proliferation, and how it responds to environmental cues such as nutrient availability and stress. Writing in Nature Cell Biology, Fumagalli et al.3 provide insight not only into the molecular mechanisms that connect ribosome biogenesis and cell proliferation, but also into underlying human diseases associated with defective ribosome synthesis — ribosomopathies4,5.
Eukaryotic organisms (such as yeast, plants and animals) have two ribosomal subunits, 60S and 40S, which are assembled in the nucleolus — a nuclear structure that specializes in ribosome production — before being exported to the cytoplasm. Previous work has shown that, on disruption of the nucleolus, ribosome synthesis is impaired, leading to a halt in the cell cycle6,7,8. Unexpectedly, such nucleolar stress induces and stabilizes p53, a key regulator of cell proliferation. In fact, on disintegration of the nucleolus, several ribosomal proteins are released into the nucleoplasm and bind to the enzyme MDM2. This E3 ubiquitin ligase normally promotes p53 degradation, but, when bound to ribosomal proteins, it no longer functions properly. As a result, p53 levels rise, causing cell-cycle arrest, apoptotic cell death and/or senescence6,7,8.
Fumagalli et al.3 specifically disrupt the formation of the 40S subunit using RNA interference, without disrupting the nucleolus. In agreement with another recent study9, they find that, even in the presence of an intact nucleolus, both p53 stabilization and the subsequent cell-cycle arrest occur. Strikingly, regardless of whether biogenesis of the 60S or the 40S sub-unit is impaired, it is a 60S protein component, L11, that mediates p53 stabilization by binding to MDM2. But, whereas defects in 60S biogenesis are expected to lead to an increase in free L11, how can impaired formation of 40S yield this protein?
The authors3 show that disruption of 40S biogenesis activates the translation of a group of messenger RNAs called 5'-TOP mRNAs — including the L11 mRNA — which contain a sequence motif of several pyrimidine bases in their 5'-untranslated regions. So free L11 can be generated in two ways: its mRNA translation increases when 40S biogenesis is impaired; and it is independently released into the nucleoplasm when 60S biogenesis is defective (Fig. 1). It remains to be seen how the translation machinery senses disruption in 40S biogenesis.
Fumagalli and colleagues' observations3 unravel an exciting direct link between ribo-somal stress and p53 induction, which will undoubtedly stimulate further investigation. Earlier work6,7 has indicated that, as well as L11, other ribosomal proteins from both 40S and 60S can bind to MDM2 to stabilize p53. With L11 having the pivotal role in p53 stabilization, what contribution do these other proteins make? Moreover, because L11 assembly onto the nascent 60S subunit occurs early on in the nucleolus1,2, how would defects in the biogenesis of this subunit later on, downstream of L11 assembly, generate the p53-stabilizing form of L11?
And can Fumagalli and co-workers' findings help in understanding the ribosomopathies at the molecular level? Notably, genes encoding protein components of 60S, including L5 and L11 (ref. 10), are mutated in some patients with Diamond-Blackfan anaemia. It is important to establish whether p53 is induced in the cells of such patients. If so, how could p53 be stabilized when L11 is mutated? If p53 is indeed stabilized in these patients, the combined effects of altered p53 levels and imbalance in ribosome assembly may cause this ribosomopathic anaemia. Systematically analysing the factors involved in the crosstalk between p53 stabilization and ribosome stress will undoubtedly aid in identifying specific molecular culprits.
If p53 stabilization does turn out to be a hallmark of ribosomopathies, targeted drug therapies in patients with these conditions will require keeping a balance between sufficient ribosome formation and adequate p53 safeguarding functions. With our growing understanding of ribosome synthesis and function, and characterization of the molecular basis of ribosomopathies, the development of targeted treatments for these diseases is looking closer than ever.
About this article
Enhanced Sensitivity of Nucleoli in Human Proliferating Cells to Inhibition of Protein Synthesis with Anisomycin
Bulletin of Experimental Biology and Medicine (2010)