The Interplay Between the Oncogene and Ribosomal Proteins in Osteosarcoma Onset and Progression: Potential Mechanisms and Indication of Candidate Therapeutic Targets.

High-grade osteosarcoma (OS) is the most common primary bone tumor mainly affecting children and young adults. First-line treatment consists of neo-adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate and surgery. The mean long-term survival rate for localized disease at diagnosis is 65-70%, dropping down to 20% when metastases are present at diagnosis.

Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells.

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation.

Mutational analysis of ribosomal proteins in a cohort of pediatric patients with T-cell acute lymphoblastic leukemia reveals Q123R, a novel mutation in RPL10.

T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL involving the malignant expansion of T-cell progenitors. It is driven by a number of different possible genetic lesions, including mutations in genes encoding for ribosomal proteins (RPs). These are structural constituents of ribosomes, ubiquitous effectors of protein synthesis.

Reduction of nucleolar NOC1 leads to the accumulation of pre-rRNAs and induces Xrp1, affecting growth and resulting in cell competition.

NOC1 is a nucleolar protein necessary in yeast for both transport and maturation of ribosomal subunits. Here, we show that Drosophila NOC1 (annotated CG7839) is necessary for rRNAs maturation and for a correct animal development. Its ubiquitous downregulation results in a dramatic decrease in polysome level and of protein synthesis.

Exploitation of the ribosomal protein L10 R98S mutation to enhance recombinant protein production in mammalian cells.

Mammalian cells are commonly used to produce recombinant protein therapeutics, but suffer from a high cost per mg of protein produced. There is therefore great interest in improving protein yields to reduce production cost. We present an entirely novel approach to reach this goal through direct engineering of the cellular translation machinery by introducing the R98S point mutation in the catalytically essential ribosomal protein L10 (RPL10-R98S).

DKC1 Overexpression Induces a More Aggressive Cellular Behavior and Increases Intrinsic Ribosomal Activity in Immortalized Mammary Gland Cells.

Dyskerin is a nucleolar protein involved in the small nucleolar RNA (snoRNA)-guided pseudouridylation of specific uridines on ribosomal RNA (rRNA), and in the stabilization of the telomerase RNA component (hTR). Loss of function mutations in DKC1 causes X-linked dyskeratosis congenita, which is characterized by a failure of proliferating tissues and increased susceptibility to cancer. However, several tumors show dyskerin overexpression.

Ribosomal Protein L10: From Function to Dysfunction.

Eukaryotic cytoplasmic ribosomes are highly structured macromolecular complexes made up of four different ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs), which play a central role in the decoding of genetic code for the synthesis of new proteins. Over the past 25 years, studies on yeast and human models have made it possible to identify (ribosomal protein L10 gene), which is a constituent of the large subunit of the ribosome, as an important player in the final stages of ribosome biogenesis and in ribosome function. Here, we reviewed the literature to give an overview of the role of RPL10 in physiologic and pathologic processes, including inherited disease and cancer.

Combined expression levels of KDM2A and KDM2B correlate with nucleolar size and prognosis in primary breast carcinomas.

Ribosome biogenesis is a fine-tuned cellular process and its deregulation is linked to cancer progression: tumors characterized by an intense ribosome biogenesis often display a more aggressive behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, the higher one being the epigenetic regulation of the condensation of chromatin portions containing rRNA genes. KDM2A and KDM2B (Lysine (K)-specific demethylase 2A / B) are histone demethylases modulating the accessibility of ribosomal genes, thereby regulating their transcription.

Separated Siamese Twins: Intronic Small Nucleolar RNAs and Matched Host Genes May be Altered in Conjunction or Separately in Multiple Cancer Types.

Small nucleolar RNAs (snoRNAs) are non-coding RNAs involved in RNA modification and processing. Approximately half of the so far identified snoRNA genes map within the intronic regions of host genes, and their expression, as well as the expression of their host genes, is dependent on transcript splicing and maturation. Growing evidence indicates that mutations and/or deregulations that affect snoRNAs, as well as host genes, play a significant role in oncogenesis.

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism.

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6).

The Ribosome Biogenesis-Cancer Connection.

Multifaceted relations link ribosome biogenesis to cancer. Ribosome biogenesis takes place in the nucleolus. Clarifying the mechanisms involved in this nucleolar function and its relationship with cell proliferation: 1) allowed the understanding of the reasons for the nucleolar changes in cancer cells and their exploitation in tumor pathology, 2) defined the importance of the inhibition of ribosome biogenesis in cancer chemotherapy and 3) focused the attention on alterations of ribosome biogenesis in the pathogenesis of cancer.

Turning Uridines around: Role of rRNA Pseudouridylation in Ribosome Biogenesis and Ribosomal Function.

Ribosomal RNA (rRNA) is extensively edited through base methylation and acetylation, 2'-O-ribose methylation and uridine isomerization. In human rRNA, 95 uridines are predicted to by modified to pseudouridine by ribonucleoprotein complexes sharing four core proteins and differing for a RNA sequence guiding the complex to specific residues to be modified. Most pseudouridylation sites are placed within functionally important ribosomal domains and can influence ribosomal functional features.

RNA Pseudouridylation in Physiology and Medicine: For Better and for Worse.

Pseudouridine is the most abundant modification found in RNA. Today, thanks to next-generation sequencing techniques used in the detection of RNA modifications, pseudouridylation sites have been described in most eukaryotic RNA classes. In the present review, we will first consider the available information on the functional roles of pseudouridine(s) in different RNA species.

Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells.

The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription.

The importance of being (slightly) modified: The role of rRNA editing on gene expression control and its connections with cancer.

In human ribosomal RNAs, over 200 residues are modified by specific, RNA-driven enzymatic complexes or stand-alone, RNA-independent enzymes. In most cases, modification sites are placed in specific positions within important functional areas of the ribosome. Some evidence indicates that the altered control in ribosomal RNA modifications may affect ribosomal function during mRNA translation.

A reconstituted cell-free assay for the evaluation of the intrinsic activity of purified human ribosomes.

We describe a cell-free translation system for evaluating the activity of ribosomes stringently purified from human cells. This system is based on in vitro reconstitution of the cellular translation machinery, in which a ribosome-free rabbit reticulocyte lysate (RRL) is reassembled with human ribosomes and in vitro-transcribed reporter mRNAs. The protocol describes the preparation of the RRL-derived fractions, purification of ribosomes devoid of detectable nonribosomal-associated factors, and assembly of the reactions to evaluate ribosomal translational efficiency and fidelity using appropriate reporter transcripts.

Dyskerin and TERC expression may condition survival in lung cancer patients.

Dyskerin mediates both the modification of uridine on ribosomal and small nuclear RNAs and the stabilization of the telomerase RNA component (TERC). In human tumors dyskerin expression was found to be associated with both rRNA modification and TERC levels. Moreover, dyskerin overexpression has been linked to unfavorable prognosis in a variety of tumor types, however an explanation for the latter association is not available.