Ribosomopathies: how a common root can cause a tree of pathologies

Abstract

Defects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. Ribosomes are composed of ribosomal proteins (RPs) and ribosomal RNA (rRNA). RPs and multiple other factors are necessary for the processing of pre-rRNA, the assembly of ribosomal subunits, their export to the cytoplasm and for the final assembly of subunits into a ribosome. Haploinsufficiency of certain RPs causes DBA, whereas mutations in other factors cause various other ribosomopathies. Despite the general nature of their underlying defects, the clinical manifestations of ribosomopathies differ. In DBA, for example, red blood cell pathology is especially evident. In addition, individuals with DBA often have malformations of limbs, the face and various organs, and also have an increased risk of cancer. Common features shared among human DBA and animal models have emerged, such as small body size, eye defects, duplication or overgrowth of ectoderm-derived structures, and hematopoietic defects. Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways. The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies. Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

A Puzzle of Life: Crafting Ribosomal Subunits

“…Whereas severe mutations in r-proteins will produce non-functional ribosomes, milder mutations may cause biogenesis and/or translation defects. In humans, reduced translation efficiency or accuracy may lead to ribosomopathies, whose clinical characteristics often include anemia or developmental defects [44][45][46][47]. Moreover, defects in ribosome assembly increase the levels of free r-proteins, acting as a signal for ribosome biogenesis stress.…”

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

“…Those associating with the 40S subunit are referred to as RPSs or small ribosomal subunit proteins, while those associating with the 60S subunit are referred to as RPLs or large ribosomal subunit proteins [66,70] . Several lines of evidence indicate that the main purpose of the RPs is to stabilize rRNA folding and structure, thus assisting in processing: (i) the RPs are RNA-binding proteins which are dependent on RNA structure and conformation, (ii) there are very few protein-protein interactions between the RPs, (iii) while many of the RPs possess a tail which inserts into the ribosome core, the core is mostly hollow, with the exception of the rRNA species, and these protein tails do not interact with the mRNA substrate [66] .…”

“…Others have been demonstrated to bind to the untranslated regions of mRNAs resulting in changes in mRNA stability or other transcript-specific outcomes. RPL40 is required for the efficient translation of many stress response proteins as well as vesticular stomatitis virus (VSV) mRNA, and RPL38 has been shown to affect the translation of some homeobox mRNAs [70] .…”

“…biogenesis results in a pro-apoptotic state in affected cells apparently through the augmentation of p53 expression [70] .…”

“…Under growth conditions mTOR activity favors the enhanced expression of both RPs and the RNA polymerases resulting in sufficient expression of the components necessary for the ribosome biosynthesis. Under stress conditions, reduced mTOR activity and phosphorylation of eIF2α results in reduced translation and expression of the polymerases as well as the RPs [2,70] . Interestingly, under the conditions of haploinsufficiencies of the RPs, the process of pre-rRNA maturation is altered resulting in an increasing pool of unassimilated RPs.…”