Defective ribosome assembly in Shwachman-Diamond syndrome

Wong, Chi Chun; Traynor, David; Basse, Nicolas; Kay, Robert R.; Warren, Alan J.

doi:10.1182/blood-2011-06-353938

Cited by 139 publications

(155 citation statements)

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“…Work in yeast (Menne et al, 2007), mouse liver (Finch et al, 2011), Dictyostelium and SDS patient lymphoblasts (Wong et al, 2011) has suggested a role for Sbds in late ribosome assembly, with loss of Sbds function resulting in a subunit joining defect. To identify whether our Sbds ATG MO-injected embryos exhibited similar ribosome assembly defects, we generated ribosome profiles at 48 hpf under native polysome assembly conditions.…”

Section: Knockdown Of Zebrafish Sbds Recapitulates the Developmental mentioning

confidence: 99%

“…SBDS is a highly conserved, essential gene that functions in late maturation of the large 60S ribosomal subunit. Studies in a variety of organisms and SDS patient lymphoblasts suggest that mutations in SBDS result in ribosomal subunit joining defects associated with altered subunit ratios (Zhang et al, 2006;Menne et al, 2007;Finch et al, 2011;Wong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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Section: Knockdown Of Zebrafish Sbds Recapitulates the Developmental mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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“…3), a cytoplasmic series of events culminating in the functional interaction between EFL1 and SBDS on nascent 60S ribosomal subunits catalyzes eIF6 release, possibly through the generation of a conformation change in the ribosome. 3,18,20 eIF6 "gainof-function" mutants can rescue mutations in SBDS and EFL1 genes in yeast, 21,22 Dictyostelium, 20 murine and human cells. 18,21 It is unclear whether eIF6, once released in the last step of 60S maturation can rebind 60S in vivo (in vitro eIF6 binds mature ribosomes efficiently).…”

Section: Translationmentioning

confidence: 99%

“…SBDS cooperates with the GTPase EFL1 to trigger eIF6 release from nascent 60S ribosomal subunits. 18,20,21 This process permitting the release of eIF6 from 60S subunits and subsequent 80S ribosome assembly is corrupted in SDS. 18 Taken together, these observations indicate that 60S availability and/or 80S formation are actively controlled by eIF6 and are crucial in disease.…”

confidence: 99%

Translational control by 80S formation and 60S availability: The central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis

Brina¹,

Grosso²,

Miluzio³

et al. 2011

Cell Cycle

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“…Syo1 facilitates the synchronized import of the two 5S rRNA-binding proteins, Rpl5 and Rpl11, to ensure stoichiometric the incorporation of these two proteins into the pre-60S subunits and also works as an assembly platform for the 5S ribonucleoprotein (RNP) (11,12). Release of the anti-association factor Tif6 requires elongation factor-like Efl1 and tRNAlike Sdo1 to confirm the integrity of the P-site (13)(14)(15). Transacting factors on cytoplasmic pre-40S subunits not only prevent them from joining translation (16) but also perform a translation-like cycle to ensure the quality of the 40S subunits prior to actual translation of mRNA (17).…”

mentioning

confidence: 99%

The Roles of Puf6 and Loc1 in 60S Biogenesis Are Interdependent, and Both Are Required for Efficient Accommodation of Rpl43

Yang

Ting

Liang

et al. 2016

Journal of Biological Chemistry

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Puf6 and Loc1 have two important functional roles in the cells, asymmetric mRNA distribution and ribosome biogenesis. Puf6 and Loc1 are localized predominantly in the nucleolus. They bind ASH1 mRNA, repress its translation, and facilitate the transport to the daughter cells. Asymmetric mRNA distribution is important for cell differentiation. Besides their roles in mRNA localization, Puf6 and Loc1 have been shown to be involved in 60S biogenesis. In puf6⌬ or loc1⌬ cells, pre-rRNA processing and 60S export are impaired and 60S subunits are underaccumulated. The functional studies of Puf6 and Loc1 have been focused on ASH1 mRNA pathway, but their roles in 60S biogenesis are still not clear. In this study, we found that Puf6 and Loc1 interact directly with each other and both proteins interact with the ribosomal protein Rpl43 (L43e). Notably, the roles of Puf6 and Loc1 in 60S biogenesis are interdependent, and both are required for efficient accommodation of Rpl43. Loc1 is further required to maintain the protein level of Rpl43. Additionally, the recruitment of Rpl43 is required for the release of Puf6 and Loc1. We propose that Puf6 and Loc1 facilitate Rpl43 loading and are sequentially released from 60S after incorporation of Rpl43 into ribosomes in yeast.Almost every process in a cell is mediated by proteins, the products of translating mRNA by ribosomes. Ribosomes are composed of two subunits, a small subunit and a large subunit, 40S and 60S, respectively, in eukaryotic cells. In Saccharomyces cerevisiae, the 40S and 60S subunits are assembled from a large primary 35 S rRNA transcribed by RNA polymerase I. Processing of this rRNA yields 5.8S, 18S, and 25S rRNAs. The 5S rRNA is transcribed by RNA polymerase III separately (see reviews in Refs. 1-4). In yeast, 5S, 5.8S, and 25S (28S in higher eukaryotes) rRNA assemble with 39 ribosomal proteins to make up the 60S subunit, whereas 18S rRNA and 33 ribosomal proteins constitute the 40S subunit (5-7).Ribosome biogenesis is necessary for cell growth and proliferation. The synthesis of ribosome is a complex pathway in which over 200 trans-acting factors are involved. Many of the RNA folding, protein assembly, and maturation events are hierarchical, requiring the correct completion of one event to progress to the next event. This is seen in the assembly of ribosomal proteins onto the RNA in bacterial ribosome assembly (8) as well as in cytoplasmic maturation of the large subunit in yeast (9, 10). In addition, trans-acting factors also perform quality control steps for the assembly of the protein synthesis machinery. Syo1 facilitates the synchronized import of the two 5S rRNA-binding proteins, Rpl5 and Rpl11, to ensure stoichiometric the incorporation of these two proteins into the pre-60S subunits and also works as an assembly platform for the 5S ribonucleoprotein (RNP) (11,12). Release of the anti-association factor Tif6 requires elongation factor-like Efl1 and tRNAlike Sdo1 to confirm the integrity of the P-site (13-15). Transacting factors on cytoplasmic pre-40S subuni...

show abstract

Defective ribosome assembly in Shwachman-Diamond syndrome

Cited by 139 publications

References 35 publications

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Translational control by 80S formation and 60S availability: The central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis

The Roles of Puf6 and Loc1 in 60S Biogenesis Are Interdependent, and Both Are Required for Efficient Accommodation of Rpl43

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