3 years ago

Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes

Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes
Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5′TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5′TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5′TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5′TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q syndrome.

Graphical abstract

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Teaser

Ribosomal proteins (RPs) are essential components of the translational machinery. Gentilella et al. show that the 40S ribosome and LARP1 form a complex that has a high affinity for 5′TOP mRNAs, particularly RPs. This association preserves 5′TOP mRNA stability, constituting an anabolic reservoir that can be utilized upon demand.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304070

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