Control of nucleolar stress and translational reprogramming by lncRNAs

Under adverse environmental conditions, cells activate stress responses that favour adaptation or, in case of irreversible damage, induce cell death. Multiple stress response pathways converge to downregulate ribosome biogenesis and translation since these are the most energy consuming processes in the cell. This adaptive response allows preserving genomic stability and saving energy for the recovery. It follows that the nucleolus is a major sensor and integrator of stress responses that are then transmitted to the translation machinery through an intricate series of conserved events. Long non-coding RNAs (lncRNAs) are emerging as important regulators of stress-induced cascades, for their ability to mediate post-transcriptional responses. Consistently, many of them are specifically expressed under stress conditions and a few have been already functionally linked to these processes, thus further supporting a role in stress management. In this review we survey different archetypes of lncRNAs specifically implicated in the regulation of nucleolar functions and translation reprogramming during stress responses

Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3

Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINCO2657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells

Legal assessment explaining why COPA*COGECA's objections against the Nature Restoration Act proposal are misleading

In their letter of 26 June 2023 Copa*Cogeca asked the members of the European Parliament’s Committee on Environment to reject the Nature Restoration Law proposal. They based their arguments for this rejection on what they considered as ‘red line’ issues, which makes the law proposal unacceptable to them.As Legal Working Group (LWG) from SERE , we analysed these ‘red line’ issues and we concluded that their red line objections against the Nature Restoration Law proposal cannot withstand legal scrutiny. Many of their concerns are already present in the Commission proposal and are further addressed in the Swedish presidency compromise proposal. Further weakening of the Nature Restoration Law is against existing EU legislation

Legal assessment explaining why COPA*COGECA's objections against the Nature Restoration Act proposal are misleading

In their letter of 26 June 2023 Copa*Cogeca asked the members of the European Parliament’s Committee on Environment to reject the Nature Restoration Law proposal. They based their arguments for this rejection on what they considered as ‘red line’ issues, which makes the law proposal unacceptable to them.As Legal Working Group (LWG) from SERE , we analysed these ‘red line’ issues and we concluded that their red line objections against the Nature Restoration Law proposal cannot withstand legal scrutiny. Many of their concerns are already present in the Commission proposal and are further addressed in the Swedish presidency compromise proposal. Further weakening of the Nature Restoration Law is against existing EU legislation

Legal assessment of the Proposal for an EU Nature Restoration Law:Report by the Legal Working Group of the Society for Ecological Restoration Europe

This assessment is based on the Commission proposal for a Nature Restoration Law (hereafter referred to as NRL) from 22 June 2022.2 The Legal Working Group is aware that the proposal is currently being discussed by the Council and Parliament. It is therefore not an article-by-article assessment, but a more general assessment of several legal aspects of the law we consider to be particularly important. Our choice of the discussed aspects was based on ongoing political discussions on the law (e.g. in the EU parliament and Council). The note gives legal arguments why certain articles should remain in the law or should be amended or added to the law. Legal arguments include legal certainty for stakeholders, coherence with other EU legislation, legitimate expectations, accepted legal principles, etc. Where relevant, we include concrete suggestions for amending and improving the law proposal.<br/

mTor inhibitor GDC-0349 improves ASO induced SAMMSON knock down resulting in enhanced anti-tumor efficacy in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. The lack of an effective treatment results in a median survival time of less than one year for patients with metastatic disease and shows the high unmet need for the development of effective treatments. Recently, the melanoma-specific lncRNA SAMMSON was shown to be essential for skin melanoma survival. Analysis of a PAN cancer RNA-sequencing dataset revealed consistent expression of SAMMSON in uveal melanoma tumors. Targeting SAMMSON by means of antisense oligonucleotides (ASOs) results in a strong reduction in cell viability with induction of apoptosis of UM cells and slows down tumor growth in multiple UM PDX models. These effects were driven by impaired mitochondrial function and protein translation, resulting in cell death. To identify potential synergistic combinations, we combined SAMMSON knockdown with a library of 2911 FDA-approved drugs and quantified cell viability in a uveal melanoma cell line. The strongest synergy was obtained with the mTOR inhibitor GDC-0349. Combining SAMMSON knockdown with mTOR inhibition resulted in enhanced impairment of mitochondrial function and protein synthesis. Interestingly, we observed a more pronounced knockdown of SAMMSON when combining SAMMSON targeting ASOs with GDC-0349, suggesting mTOR inhibition facilitates ASO uptake in uveal melanoma cells. Further experiments are ongoing to confirm this mechanism. Taken together, these results demonstrate that SAMMSON inhibition in combination with mTOR inhibition could be a novel treatment option for uveal melanoma patients

Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1

RNA 3' end processing provides a source of transcriptome diversification which affects various (patho)-physiological processes. A prime example is the transcript isoform switch that leads to the read-through expression of the long non-coding RNA NEAT1_2, at the expense of the shorter polyadenylated transcript NEAT1_1. NEAT1_2 is required for assembly of paraspeckles (PS), nuclear bodies that protect cancer cells from oncogene-induced replication stress and chemotherapy. Searching for proteins that modulate this event, we identified factors involved in the 3' end processing of polyadenylated RNA and components of the Integrator complex. Perturbation experiments established that, by promoting the cleavage of NEAT1_2, Integrator forces NEAT1_2 to NEAT1_1 isoform switching and, thereby, restrains PS assembly. Consistently, low levels of Integrator subunits correlated with poorer prognosis of cancer patients exposed to chemotherapeutics. Our study establishes that Integrator regulates PS biogenesis and a link between Integrator, cancer biology, and chemosensitivity, which may be exploited therapeutically

SAMMSON fosters cancer cell fitness by concertedly enhancing mitochondrial and cytosolic translation

Synchronization of mitochondrial and cytoplasmic translation rates is critical for the maintenance of cellular fitness, with cancer cells being especially vulnerable to translational uncoupling. Although alterations of cytosolic protein synthesis are common in human cancer, compensating mechanisms in mitochondrial translation remain elusive. Here we show that the malignant long non-coding RNA (lncRNA) SAMMSON promotes a balanced increase in ribosomal RNA (rRNA) maturation and protein synthesis in the cytosol and mitochondria by modulating the localization of CARF, an RNA-binding protein that sequesters the exo-ribonuclease XRN2 in the nucleoplasm, which under normal circumstances limits nucleolar rRNA maturation. SAMMSON interferes with XRN2 binding to CARF in the nucleus by favoring the formation of an aberrant cytoplasmic RNA-protein complex containing CARF and p32, a mitochondrial protein required for the processing of the mitochondrial rRNAs. These data highlight how a single oncogenic lncRNA can simultaneously modulate RNA-protein complex formation in two distinct cellular compartments to promote cell growth

Escaping BRAF inhibition: A "linc" with non-coding RNAs?

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Cancer development and therapy resistance: spotlights on the dark side of the genome

Cancer research has been focusing so far on genetic alterations in protein-coding genes. However, mounting evidence underlines the importance of epigenetic and post-transcriptional events in cancer progression and therapy resistance. Moreover, recent genome-wide studies show that disease-causing mutations and chromosome rearrangements often span areas of the genome that do not contain any known protein-coding gene. This finding is not surprising, considering that even though the vast majority of the human genome is transcribed, only a minor portion (accounting for less than 2%) encodes for proteins. Among the various classes of transcribed RNAs, long non-coding RNAs are attractive biomarkers and therapeutic targets due to their disease- and stage-restricted expression. In addition, by taking part in all the major epigenetic and post-transcriptional programs in the cell, long non-coding RNAs are emerging as key regulators of stress responses and therefore they are important non-genetic players in cancer development and progression. Here I discuss the role of lncRNAs in cancer and their promises and pitfalls as biomarkers and therapeutic targets.status: publishe