Ribosomopathies: human disorders of ribosome dysfunction

Narla, Anupama; Ebert, Benjamin L.

doi:10.1182/blood-2009-10-178129

Cited by 698 publications

(753 citation statements)

References 102 publications

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“…23 Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes such as Treacher Collins syndrome, dyskeratosis congenita, cartilage-hair hypoplasia and Schwachman-Diamond syndrome. 24 Acquired abnormalities in ribosome function have also been implicated more broadly in human malignancies. 25 Although it is accepted that proteotoxic stress triggers substantial alterations in rRNA biogenesis, its specific effects are variable depending on drug concentrations, cell lines and kinetics of treatments.…”

Section: Discussionmentioning

confidence: 99%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

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TRAF and TNF receptor-associated protein (TTRAP) is a multifunctional protein that can act in the nucleus as a 5 0 -tyrosyl DNA phosphodiesterase and in the cytoplasm as a regulator of cell signaling. In this paper we show that in response to proteasome inhibition TTRAP accumulates in nucleolar cavities in a promyelocytic leukemia protein-dependent manner. In the nucleolus, TTRAP contributes to control levels of ribosomal RNA precursor and processing intermediates, and this phenotype is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Our findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. Cell Death and Differentiation (2012) 19, 488-500; doi:10.1038/cdd.2011; published online 16 September 2011 TRAF and TNF receptor-associated protein (TTRAP) is a 5 0 -tyrosyl DNA phosphodiesterase that is required for the repair of topoisomerase2-induced DNA double-strand breaks. 1 It is a member of the endonuclease/exonuclease/ phosphatase family of proteins containing an Mg(2 þ )-dependent apurinic/apyrimidinic endonuclease Ape1-like domain. 2 Various yeast-two hybrid (Y2H) screenings and functional studies have unveiled TTRAP ability to interact with TNF receptors (TNFR) family members and TNFR-associated factors (TRAFs), especially TRAF6. 3 Furthermore, TTRAP was isolated as ETS-associated protein II 4 and as alk4-and smad3-binding protein. 5 Interestingly, TTRAP sequence contains a SUMO-interacting motif (SIM) that is required for its high affinity binding to SUMO-2/3. 6 TTRAP may thus has a role in the cytoplasm as a signaling molecule and in the nucleus as a DNA damage response protein and transcriptional regulator. In this context, its potential interaction with promyelocytic leukemia protein (PML), as previously determined in Y2H, suggests that TTRAP is a PML nuclear bodies (PML-NBs)-associated protein. 7 It remains unclear whether its 5 0 -tyrosyl DNA phosphodiesterase activity may account for all TTRAP biological functions.According to the cellular context, TTRAP may either protect cells from apoptosis or promote death. [8][9][10] When human SH-SY5Y cells are stressed by low doses of proteasome inhibitors, TTRAP is neuroprotective. In these conditions, endogenous TTRAP relocalizes to the cytoplasm and forms aggresome-like inclusions.In this paper we show that in response to high doses of proteasome inhibitors, TTRAP localizes to the nucleolus. This accumulation requires the association to PML-NBs and occurs in nucleolar cavities, a compartment devoid of markers of the 'ribosomal nucleolus'. Lack of TTRAP alters the levels of precursor ribosomal RNA (pre-rRNA) and processing intermediates, suggesting a new role of the PML-NBs-associated protein TTRAP in rRNA biogenesis. This function is dependent on TTRAP SIM motif, but is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Altogether, these data suggest a novel function for TTRAP and nucleolar cavities in controlling rRNA biogenesis in response to proteasome inhibiti...

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Section: Discussionmentioning

confidence: 99%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

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“…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.…”

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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“…Several other ribosomopathies predispose, albeit with weak penetrance, to MDS and AML including Shwachman-Diamond Syndrome [60], dyskeratosis congenita [61] and DiamondBlackfan anemia [62]. The importance of the effect of DDX41 mutation via ribosome biogenesis on cell growth in the leukemogenic process remains to be determined.…”

Section: Ddx41 In Post-transcriptional Regulation Of Translation Andmentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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Ribosomopathies: human disorders of ribosome dysfunction

Cited by 698 publications

References 102 publications

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

A Puzzle of Life: Crafting Ribosomal Subunits

Myeloid neoplasms with germline DDX41 mutation

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