Specialized ribosomal protein genes promote drug resistance through modulation of translation
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ABSTRACT:
PROVIDER: PRJNA551484 | ENA |
REPOSITORIES: ENA
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Project description:Ribosomes are ubiquitous ribonucleoprotein complexes required for protein synthesis. We show that in budding yeast exposure to drugs alters ribosome composition leading to modification of translation pattern and increased resistance to drug. Exposure to staurosporine repressed translation of cell wall protein genes. Expression of the major paralog of uL30/RPL7 increased cell sensitivity to staurosporine while expression of the minor paralog induced resistance. Remarkably, we found that differences in paralogs function was due to difference in the translation pattern. The minor paralog promoted the translation of cell wall genes with long open reading frames (ORFs), which are normally under-translated in the presence of the major paralog, leading to drug resistance. Reducing the ORF length repressed the minor paralog and staurosporine effects on translation. Together the data reveal a natural mechanism for the optimization of translation through changes in the identity of ribosomal protein genes.
2020-03-09 | GSE133457 | GEO
Project description:Ribosomes are often seen as monolithic machines produced from uniformly regulated genes. However, in yeast most ribosomal proteins come from duplicated genes. Here, we demonstrate that gene duplication may serve as an adaption mechanism modulating the global proteome through the differential expression of ribosomal proteins paralogs after exposure to stress. Our data indicate that the yeast paralog pair of the ribosomal protein L7/uL30 produces two differentially acetylated proteins. Under normal conditions most ribosomes incorporate the hypo-acetylated major form favoring the translation of genes with short open reading frames. Exposure to drugs, on the other hand, increases the production of ribosomes carrying the hyper-acetylated minor paralog that increases translation of long reading frames. Many of these long genes encode cell wall proteins that increase drug resistance in a programed change in translation equilibrium. Together the data reveal a mechanism of translation control through the differential fates of near-identical ribosomal protein isoforms.
2022-08-09 | GSE202803 | GEO
Project description:Ribosomes are often seen as monolithic machines produced from uniformly regulated genes. However, in yeast most ribosomal proteins come from duplicated genes. Here, we demonstrate that gene duplication may serve as a stress-adaptation mechanism modulating the global proteome through the differential expression of ribosomal protein paralogs. Our data indicate that the yeast paralog pair of the ribosomal protein L7/uL30 produces two differentially acetylated proteins. Under normal conditions most ribosomes incorporate the hypo-acetylated major form favoring the translation of genes with short open reading frames. Exposure to drugs, on the other hand, increases the production of ribosomes carrying the hyper-acetylated minor paralog that increases translation of long open reading frames. Many of these paralogs dependent genes encode cell wall proteins that could promote tolerance to drugs as their translation increases after exposure to drugs. Together the data reveal a mechanism of translation control through the differential use of near-identical ribosomal protein isoforms.
2022-08-09 | PXD033843 | Pride
Project description:We report that 2’-O-methylation levels at subset of positions in human ribosomal RNA are variable between cell types and conditions, and that the degree of methylation at distinct sites is responsive to key cellular pathways. MYC overexpression results in increased methylation at a particular rRNA site (18S:C174). We find that this methylation is important for modulating translation of distinct mRNAs, leading to phenotypic changes including modulation of cell proliferation rate. Thus, differential rRNA 2’-O-methylation can give rise to ribosomes with specialized function.
2021-08-16 | GSE153473 | GEO
Project description:We report that 2’-O-methylation levels at subset of positions in human ribosomal RNA are variable between cell types and conditions, and that the degree of methylation at distinct sites is responsive to key cellular pathways. MYC overexpression results in increased methylation at a particular rRNA site (18S:C174). We find that this methylation is important for modulating translation of distinct mRNAs, leading to phenotypic changes including modulation of cell proliferation rate.
2021-08-16 | GSE148965 | GEO
Project description:Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct ‘specialized ribosomes’ that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Whilst viruses have evolved a variety of mechanisms to overcome this, we hypothesize that some viruses manipulate the host cell to produce specialized ribosomes to preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterized KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insight into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialized ribosomes to facilitate efficient translation of viral mRNAs.
2022-12-14 | GSE199095 | GEO
Project description:RNA decay is crucial for RNA turnover and surveillance, and misregulated in many diseases. This complex system is challenging to study, particularly in mammals, where it remains unclear whether decay pathways perform specialized or redundant roles. Cytoplasmic pathways, and links to translation, are particularly enigmatic. By directly profiling targets of decay factors (XRN1, SKIV2L and MTR4) and normal/aberrant translation events in mouse embryonic stem cells, we uncovered extensive specialization between decay pathways and crosstalk with translation. XRN1 (5’-3’) mediated cytoplasmic bulk mRNA turnover whereas SKIV2L (3’-5’) was universally recruited by ribosomes, tackling aberrant translation and sometimes modulating mRNA abundance. Further exploring translation surveillance, we identified AVEN and FOCAD as SKIV2L interactors. AVEN prevented ribosome stalls at structured regions, which otherwise required SKIV2L for clearance. This pathway was crucial for histone translation, uORF regulation and counteracting spurious non-coding RNA translation. In summary, we identified key targets, components and functions of mammalian RNA decay pathways, and uncovered extensive coupling to translation.
2020-01-29 | GSE134020 | GEO
Project description:Regulation of translation by site-specific ribosomal RNA methylation.
| PRJNA642792 | ENA
Project description:Diamond Blackfan Anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (e.g. Rps19) or large (e.g. Rpl11) ribosomal subunit are found in over half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced expression of *Rps19* or *Rpl11* in mouse erythroblasts and investigated mRNA polyribosome association, which revealed deregulated translation initiation of specific transcripts. Among these were *Bag1*, encoding a Hsp70 co-chaperone, and *Csde1*, encoding an RNA binding protein, both expressed at increased levels in erythroblasts. Their translation initiation is cap-independent and starts from an internal ribosomal entry site (IRES), which appeared sensitive to knock down of Rps19 or Rpl11. Mouse embryos lacking Bag1 die at embryonic day E13.5 with reduced erythroid colony forming cells in the fetal liver, and low Bag1 expression impairs erythroid differentiation in vitro. Reduced expression of Csde1 impairs proliferation and differentiation of erythroid blasts. Protein but not mRNA expression of *BAG1* and *CSDE1* was reduced in erythroblasts cultured from DBA patients. Our data suggest that impaired IRES-mediated translation of mRNAs expressed at increased levels in erythroblasts contributes to the erythroid phenotype of DBA. 3 biological replicates of erythroblasts treated with different shRNA were used for polyribosomal sucrose gradients; RNA was extracted from gradients in 2 samples - mRNA associated with polyribosomes (poly) and the rest (sub).
2011-11-14 | E-GEOD-22903 | biostudies-arrayexpress
Project description:We conducted an in vivo genome-wide CRISPR activation screen to identify genes that accelerate distal metastasis by breast cancer patient-derived circulating tumor cells (CTCs) following direct intravascular inoculation in mice. Regulators of translation and ribosomal proteins were prominent among these, and expression of RPL15, a component of the large ribosome subunit, was sufficient to increase metastatic growth in multiple organs. RPL15 overexpression selectively increases translation of other ribosomal proteins and cell cycle regulators. Unsupervised analysis of single-cell RNA sequencing of freshly-isolated CTCs from breast cancer patients identifies a subset with strong ribosomal and protein translation signatures, correlated with increased proliferative markers, epithelial markers and poor clinical outcome. Thus, ribosome protein expression identifies an aggressive subset of CTCs, whose therapeutic targeting may suppress metastatic progression.
2020-02-07 | GSE143625 | GEO