The importance of ribosome production, and the 5S RNP–MDM2 pathway, in health and disease

Pelava, Andria; Schneider, Claudia; Watkins, Nicholas J.

doi:10.1042/bst20160106

Cited by 74 publications

(68 citation statements)

References 51 publications

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“…MDM2, an inhibitor of TP53, is directly regulated by several RPs in an essential pathway in response to nucleolar stress (135–137). In growing cells, ribosome biogenesis is fully active and free RPs are incorporated into the ribosome.…”

Section: Defects In Ribosome Biogenesis Ribosomal Proteins and Ribosmentioning

confidence: 99%

How Ribosomes Translate Cancer

et al. 2017

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A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis – from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on “onco-ribosomes” as an Achilles’ heel of cancer cells and a promising target for further therapeutic intervention.

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Section: Defects In Ribosome Biogenesis Ribosomal Proteins and Ribosmentioning

confidence: 99%

How Ribosomes Translate Cancer

et al. 2017

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“…Moreover, defects in ribosome assembly increase the levels of free r-proteins, acting as a signal for ribosome biogenesis stress. Accordingly, in multicellular organisms, elevated levels of uL5 and uL18 are functionally linked to the E3 ubiquitin ligase MDM2 leading to accumulation of its substrate p53, thereby blocking cell division [48,49]. Taking these findings together, the levels of free r-proteins are well regulated and monitored by various mechanisms, such as transcriptional regulation, association with binding partners, and degradation, to embed ribosome assembly into other cellular pathways that exert growth control.…”

Section: Providing a Balanced Supply Of Ribosomal Componentsmentioning

confidence: 99%

A Puzzle of Life: Crafting Ribosomal Subunits

Kressler

Hurt

Baßler

2017

Trends in Biochemical Sciences

165

127

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The biogenesis of eukaryotic ribosomes is a complicated process during which the transcription, modification, folding, and processing of the rRNA is coupled with the ordered assembly of $80 ribosomal proteins (r-proteins). Ribosome synthesis is catalyzed and coordinated by more than 200 biogenesis factors as the preribosomal subunits acquire maturity on their path from the nucleolus to the cytoplasm. Several biogenesis factors also interconnect the progression of ribosome assembly with quality control of important domains, ensuring that only functional subunits engage in translation. With the recent visualization of several assembly intermediates by cryoelectron microscopy (cryo-EM), a structural view of ribosome assembly begins to emerge. In this review we integrate these first structural insights into an updated overview of the consecutive ribosome assembly steps. Synopsis of Eukaryotic Ribosome AssemblyRibosomes are the molecular machines that translate the genetic information from the intermediary mRNA templates into proteins [1]. Eukaryotic 80S ribosomes comprise two unequal subunits that contain four different rRNAs and around 80 r-proteins ( Figure 1). The small 40S subunit (SSU) comprises the 18S rRNA and 33 r-proteins (referred to as RPS or S). The large 60S subunit (LSU) comprises the 25S/28S, 5.8S, and 5S rRNA and, in most eukaryotic species, 47 r-proteins (RPL or L); a notable exception is budding yeasts, which lack eL28The act of building a ribosome begins in the nucleolus, where the ribosomal DNA (rDNA) is transcribed into a long pre-rRNA precursor (35S pre-rRNA in yeast) and involves the ordered assembly of the r-proteins with the pre-rRNA, which is concomitantly processed into the mature rRNA species [5][6][7][8] (Figure 1 and Box 1). These assembly and processing events are tightly coupled and occur within preribosomal particles (see Glossary) that travel, as maturation progresses, from the nucleus across nuclear pore complexes (NPCs) to the cytoplasm, where they are ultimately converted into translation-competent ribosomal subunits [5,[9][10][11][12][13] (Figure 2, Key Figure). Given the gargantuan complexity of this process, it is unsurprising that the assembly of eukaryotic ribosomes strictly requires the assistance of a plethora (>200) of mostly essential ribosome biogenesis factors, which are also called trans-acting or assembly factors [5,14,15].Our current knowledge has been mainly obtained by studying ribosome biogenesis in the yeast Saccharomyces cerevisiae. Research conducted in the 1970s defined the r-protein composition of ribosomes, revealed the major pre-rRNA processing intermediates, and uncovered the existence of the 90S, 43S, and 66S preribosomal particles. The following 25 years witnessed the identification of numerous biogenesis factors and attributed functional roles TrendsCryoelectron microscopy analyses of the 90S preribosome show that the biogenesis factors create a casting mold that encloses the nascent pre-40S subunit.Structures of nuclear pre-60S particles reveal that a...

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“…The spliceosome and ribosome are important in the development of certain diseases (42,43). There is evidence that the spliceosome and ribosome are crucial for both GSC maintenance and early germ cell differentiation (25).…”

Section: Discussionmentioning

confidence: 99%

Small ribonucleoprotein particle protein SmD3 governs the homeostasis of germline stem cells and the crosstalk between the spliceosome and ribosome signals in Drosophila

Luan

Yan

et al. 2019

FASEB j.

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The ribonucleoprotein (RNP) spliceosome machinery triggers the precursor RNA splicing process in eukaryotes. Major spliceosome defects are implicated in male infertility; however, the underlying mechanistic links between the spliceosome and the ribosome in Drosophila testes remains largely unresolved. Small ribonucleoprotein particle protein SmD3 (SmD3) is a novel germline stem cell (GSC) regulatory gene identified in our previous screen of Drosophila testes. In the present study, using genetic manipulation in a Drosophila model, we demonstrated that SmD3 is required for the GSC niche and controls the self‐renewal and differentiation of GSCs in the testis. Using in vitro assays in Schneider 2 cells, we showed that SmD3 also regulates the homeostasis of proliferation and apoptosis in Drosophila. Furthermore, using liquid chromatography–tandem mass spectrometry methods, SmD3 was identified as binding with ribosomal protein (Rp)L18, which is a key regulator of the large subunit in the ribosome. Moreover, SmD3 was observed to regulate spliceosome and ribosome subunit expression levels and controlled spliceosome and ribosome function via RpL18. Significantly, our findings revealed the genetic causes and molecular mechanisms underlying the stem cell niche and the crosstalk between the spliceosome and the ribosome.—Yu, J., Luan, X., Yan, Y., Qiao, C, Liu, Y., Zhao, D., Xie, B., Zheng, Q., Wang, M., Chen, W., Shen, C, He, Z., Hu, X., Huang, X., Li, H., Chen, B., Zheng, B., Chen, X., Fang, J. Small ribonucleoprotein particle protein SmD3 governs the homeostasis of germline stem cells and the crosstalk between the spliceosome and ribosome signals in Drosophila. FASEB J. 33, 8125–8137 (2019). http://www.fasebj.org

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The importance of ribosome production, and the 5S RNP–MDM2 pathway, in health and disease

Cited by 74 publications

References 51 publications

How Ribosomes Translate Cancer

How Ribosomes Translate Cancer

A Puzzle of Life: Crafting Ribosomal Subunits

Small ribonucleoprotein particle protein SmD3 governs the homeostasis of germline stem cells and the crosstalk between the spliceosome and ribosome signals in Drosophila

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