Given the importance of translation in regulating protein expression in all fundamental physiologic processes, gene expression is largely controlled at the translational on top of the transcriptional level.[1] Translation is the most energy-consuming process in cells, and its dysregulation is implicated in an ever-increasing number of diseases. Evidence accrued over the past decades demonstrates that cancer [2] and neurodegenerative diseases[3,4]share defects in RNA processing or translation. Hematologic disorders are no exception.

 Ribosomes have been put in the spotlight as putative direct players in finely tuning translation by acting as mRNA filters.[5] Recent papers suggest that ribosome composition is not fixed and uniform but rather heterogeneous and modulated at the level of RP composition[6] or rRNA variants[7,8] and further modified posttranslationally or posttranscriptionally.[9,10] This ribosome heterogeneity, known as “specialized ribosome” hypothesis, could exert a direct role in mRNA selection.[11] Moreover, ribosome-associated factors[10] have been shown to possibly control translation. In addition, the number of ribosomes can play a crucial role in controlling the subset of mRNAs undergoing translation,[12] thus shaping the cellular proteome.

Recent years have led to the discovery of an increasing number of germline and somatic mutations affecting translation at multiple levels. These defects include mutations in structural constituents of the ribosomes, such as RPs, or in translation-related ncRNAs such as tRNAs (Table 1). Interestingly, in very recent years, alterations in posttranscriptional modifications of rRNA have been observed as well as deregulation of the cellular ISR and the mTOR pathways (reviewed in Tahmasebi et al.[13]).

Table1. Disorders of Translation

Classically, the best-known hematologic disorders associated with genetic mutations in genes encoding RPs or assembly factors required for ribosome biogenesis and function are called ribosomopathies. Ribosomopathies represent a range of disorders characterized by genetic abnormalities impacting on ribosome biogenesis and function. These defects cause specific clinical phenotypes and are well-known risk factors for myelodysplastic disorders and AML. Ribosomopathies can be divided into subgroups depending on where the mutation affects the ribosome.

Ribosomopathies caused by mutations in RPs most often have in common the development of bone marrow failure or anemia and/or craniofacial or other skeletal defects with an increased cancer risk later in life of the affected individual.

Commonly inherited mutations in as many as 18 diverse RP genes cause Diamond-Blackfan anemia (DBA) in children. The clinical features are erythroid hypoplasia in an otherwise normocellular marrow that manifests with a macrocytic anemia. Up to 50% of patients with DBA also have short stature, craniofacial defects, thumb abnormalities, and congenital heart malformations. Mutations in RPs (see Table 1) are identified in up to 50% of DBA patients and in general function in an autosomal dominant manner. Mutations in these genes lead to hap loinsufficiency of the corresponding RPs which causes direct defects in proper ribobiogenesis and decrease in ribosome number. Interestingly, also mutations in GATA1, a transcription factor essential in erythropoiesis, cause DBA, and, as seen in DBA with RP defects, GATA1 mRNA is more sensitive to downregulation of RPs.[14,15]

Another remarkable example of hematologic disorders connected to mutations in an RP is the 5q−-syndrome, a subtype of MDS. Haploinsufficiency of RPS14, resulting from acquisition of an interstitial deletion on chromosome 5q,[16] causes a refractory anemia very similar to DBA.

Another inherited hematologic disorder indirectly connected to translation is the Schwachman-Diamond syndrome (SDS). This syn drome is characterized by impaired hematopoiesis and neutropenia, exocrine pancreas dysfunction, and bone defects. SDS is caused by mutation in the SBDS gene, which does not encode for an RP as in the case of DBA and 5-q syndrome but which has critical function in ribosome maturation.

In addition to mutations in RPs, defects in proper posttranscriptional modifications of rRNA exist. Examples include dyskeratosis congenital (DKC), an x-linked disorder, caused by mutations in dyskerin (DKC1) which mediates pseudouridylation of rRNA. In addition to this genetic disorder, defects in other types of post transcriptional modifications of rRNA have been observed. Changes in the expression level of ncRNA involved in highly specific 2′O-methylations have been connected to B-cell lymphomas and self-renewal control of leukemia cells. Similarly, changes in expression levels of NAT10, involved in rRNA acetylation, were linked to AML (reviewed in Janin et al.[17]), further suggesting that finely tuned translational control plays a fundamental role in the hematologic pathophysiology.

In the past years, defects in tRNA processing and posttranscriptional modification have been observed both in genetic and somatic hematologic conditions. Cartilage hair hypoplasia (CHH) was first described in Amish families as a form of short-limbed dwarfism caused by skeletal dysplasia. The patients show immune dysfunction and an increased risk of acquiring non-Hodgkin lymphoma in adult hood. In addition, defects in uncommon modifications of tRNA, such as queuosine, have been found to be associated with carcinogenesis and leukemia.

Several RPs have extraribosomal functions important for cell proliferation and differentiation, DNA repair, apoptosis, and others resulting in defects independent of protein translation. Mutations affecting members of the ISR that senses cellular stresses and adapts gene expression to stress predominantly cause disorders of cells with high secretory demands, such as pancreatic cells or in neuronal cells. The mTOR pathway coordinates anabolic and catabolic processes in response to internal and external stimuli; rapamycin, an inhibitor of mTOR, inhibits translation initiation. Defects in the mTOR path way predominantly result in neurologic disorders. Both activating and loss-of-function mutations in the class IA PI3K PIK3CD or its regulatory subunit PIK3R1 cause immunodeficiency.

All ribosomopathies connected to hematologic outcomes have increased cancer risk with development of MDSs or AML, or head and neck tumors in DKC and lymphomas and basal cell carcinomas in CHH.[18] Studies suggest that translational output of the misassembled, structurally distinct ribosomes may favor translation of growth-promoting, oncogenic proteins or translation-independent regulation of oncogenes, such as MYC. Changes in ribosome composition may result in “onco-ribosomes.” In addition, ribosome defects may alter cellular protein and energy balance and create cellular stress conditions conducive to acquisition of secondary mutations. Elevated levels of reactive oxygen species (ROS) in ribosomopathies are associated with high oxidative stress and result in DNA damage and genomic instability and acquisition of cooperating mutations. Preventing the switch from hypoproliferation to hyperproliferation offers a chance to prevent cancer in patients affected by these disorders.

Despite the universal expression of ribosomal genes or ribosome related genes and ribosomal assembly factors in all tissues, the clinical presentation is dictated by the function of the affected genes and tissue-specific reliance on affected pathways. It is clear that mutations in RP genes or other proteins involved in ribosome biogenesis are causing highly specific phenotypes in specific cell types and tissues. The question as to why changes in the ubiquitous expression of these proteins and ncRNAs as well as the global requirement for protein synthesis drive specific phenotypes remains to be fully answered.

Three models prevail to explain the phenotypic variability of ribosomopathies: (1) defects in ribosome biogenesis and function result in reduced effective ribosome concentration that leads to diminished translation of a subset of mRNAs, as recently proposed for DBA[19] in certain tissues that are most sensitive to changes in ribosomal function; (2) the composition of ribosomes varies, imparting specialized ribosome function to different cell types resulting in disruption of translation of a subset of mRNAs; (3) impaired ribosome biogenesis activates the tumor suppressor p53 pathway via accumulation of unassembled RPs that bind the E3 ubiquitin-protein ligase MDM2, suppress its activity, and stabilize p53, resulting in cell cycle arrest and apoptosis.[12]

References
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[1] Schwanhäusser B, Busse D, Li N, et al. Global quantification of mammalian gene expression control. Nature. 2011;473(7347):337–342.

[2] Topisirovic I, Sonenberg N. Translation and cancer. Biochim Biophys Acta. 2015;1849(7):751–752.

[3] Patel A, Lee HO, Jawerth L, et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell. 2015;162(5): 1066–1077.

[4] Bernabò P, Tebaldi T, Groen EJN, et al. In vivo translatome profiling in spinal muscular atrophy reveals a role for SMN protein in ribosome biology. Cell Rep. 2017;21(4):953–965.

[5] Mauro VP, Edelman GM. The ribosome filter hypothesis. Proc Natl Acad Sci U S A. 2002;99(19):12031–12036.

[6] Kondrashov N, Pusic A, Stumpf CR, et al. Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell. 2011;145(3):383–397.

[7] Parks MM, Kurylo CM, Dass RA, et al. Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression. Sci Adv. 2018;4(2):eaao0665.

[8] Simsek D, Barna M. An emerging role for the ribosome as a nexus for post translational modifications. Curr Opin Cell Biol. 2017;45:92–101.

[9] Walczak CP, Leto DE, Zhang L, et al. Ribosomal protein RPL26 is the principal target of UFMylation. Proc Natl Acad Sci U S A. 2019;116(4):1299–1308.

[10] Simsek D, Tiu GC, Flynn RA, et al. The mammalian ribo-interactome reveals ribosome functional diversity and heterogeneity. Cell. 2017;169(6):1051–1065. e18.

[11] Shi Z, Fujii K, Kovary KM, et al. Heterogeneous ribosomes preferentially translate distinct subpools of mRNAs genome-wide. Mol Cell. 2017;67(1):71–83. e7.

[12] Mills EW, Green R. Ribosomopathies: there’s strength in numbers. Science. 2017;358(6363):eaan2755.

[13] Tahmasebi S, Khoutorsky A, Mathews MB, Sonenberg N. Translation deregulation in human disease. Nat Rev Mol Cell Biol. 2018;19(12):791–807.

 [14] Sankaran VG, Ghazvinian R, Do R, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond–Blackfan anemia. J Clin Invest. 2012;122(7):2439–2443.

[15] Ludwig LS, Gazda HT, Eng JC, et al. Altered translation of GATA1 in Diamond–Blackfan anemia. Nat Med. 2014;20(7):748–753.

[16] Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451(7176):335–339.

[17] Janin M, Coll-SanMartin L, Esteller M. Disruption of the RNA modifications that target the ribosome translation machinery in human cancer. Mol Cancer. 2020;19(1):70.

[18] Kampen KR, Sulima SO, Vereecke S, De Keersmaecker K. Hallmarks of ribosomopathies. Nucleic Acids Res. 2020;48(3):1013–1028.

 [19] Khajuria RK, Munschauer M, Ulirsch JC, et al. Ribosome levels selectively regulate translation and lineage commitment in human hematopoiesis. Cell. 2018;173(1):90–103. e19.

مواضيع ذات صلة

Targeting of Nuclear Proteins

The Process of Translation

RNA Granules and Membraneless Organelles

RNA Interference

Balancing Synthesis of Ribosomal Components

Regulation of Ribosome Synthesis

Proportionality of Ribosome Levels and Growth Rates

The Signal Recognition Particle and Translocation

Verifying the Signal Peptide Model

Directing Proteins to Specific Cellular Sites

Protein Elongation Rates

Messenger Instability