Systematic identification of NF90 target RNAs by iCLIP analysis

AbstractRNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNAs directing numerous essential roles in cellular physiology. Nuclear Factor 90 (NF90) is an RBP encoded by the interleukin enhancer-binding factor 3 (ILF3) gene that has been found to influence RNA metabolism at several levels, including pre-RNA splicing, mRNA turnover, and translation. To systematically identify the RNAs that interact with NF90, we carried out iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation) analysis in the human embryonic fibroblast cell line HEK-293. Interestingly, many of the identified RNAs encoded proteins involved in the response to viral infection and RNA metabolism. We validated a subset of targets and investigated the impact of NF90 on their expression levels. Two of the top targets, IRF3 and IRF9 mRNAs, encode the proteins IRF3 and IRF9, crucial regulators of the interferon pathway involved in the SARS-CoV-2 immune response. Our results support a role for NF90 in modulating key genes implicated in the immune response and offer insight into the immunological response to the SARS-CoV-2 infection.

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Novel Insights into YB-1 Signaling and Cell Death Decisions

Cancers ◽

10.3390/cancers13133306 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3306

Author(s):

Aneri Shah ◽

Jonathan A. Lindquist ◽

Lars Rosendahl ◽

Ingo Schmitz ◽

Peter R. Mertens

Keyword(s):

Stress Responses ◽

Rna Splicing ◽

Cell Cycle Progression ◽

Rna Binding ◽

Inflammatory Responses ◽

Rna Binding Proteins ◽

Inflammatory Diseases ◽

Therapeutic Option ◽

Tumor Therapy ◽

Inflammatory Microenvironment

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

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Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

Cell & Bioscience ◽

10.1186/s13578-021-00661-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xuechai Chen ◽

Jianan Wang ◽

Muhammad Tahir ◽

Fangfang Zhang ◽

Yuanyuan Ran ◽

...

Keyword(s):

Intervertebral Disc Degeneration ◽

Rna Binding ◽

Rna Binding Proteins ◽

Degradation Process ◽

Human Diseases ◽

Rna Modification ◽

Rna Methylation ◽

M6a Rna Methylation ◽

The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis

Frontiers in Oncology ◽

10.3389/fonc.2020.568469 ◽

2020 ◽

Vol 10 ◽

Author(s):

Chao Mei ◽

Pei-Yuan Song ◽

Wei Zhang ◽

Hong-Hao Zhou ◽

Xi Li ◽

...

Keyword(s):

Cutaneous Melanoma ◽

Rna Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Melanoma Prognosis ◽

Aberrant Rna

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RNA Is a Double-Edged Sword in ALS Pathogenesis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.708181 ◽

2021 ◽

Vol 15 ◽

Author(s):

Benjamin L. Zaepfel ◽

Jeffrey D. Rothstein

Keyword(s):

Motor Neurons ◽

Cortical Neurons ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Small Subset ◽

Toxic Rna ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

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The SRSF4-GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy

Circulation Research ◽

10.1161/circresaha.120.318577 ◽

2021 ◽

Author(s):

Javier Larrasa-Alonso ◽

María Villalba ◽

Carlos Martí-Gómez ◽

Paula Ortiz-Sánchez ◽

Marina López-Olañeta ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Cardiac Hypertrophy ◽

Diastolic Dysfunction ◽

Ventricular Hypertrophy ◽

Transcriptional Activity ◽

Rna Binding ◽

Rna Binding Proteins ◽

Left Ventricular ◽

Therapeutic Tools ◽

Nucleotide Resolution

Rationale: RNA-binding proteins (RBPs) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP serine/arginine-rich splicing factor 4 (SRSF4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. Objective: To investigate the role of SRSF4 in the heart. Methods and Results: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long non-coding RNAs (lncRNAs), including GAS5 (growth arrest specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotide-resolution cross-linking and immuno-precipitation (iCLIP). GAS5 is a repressor of the glucocorticoid receptor (GR) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. Conclusions: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in Cushing's syndrome patients.

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Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function

10.1101/2020.09.04.263251 ◽

2020 ◽

Cited By ~ 2

Author(s):

Fiona Haward ◽

Magdalena M. Maslon ◽

Patricia L. Yeyati ◽

Nicolas Bellora ◽

Jan N. Hansen ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Rna Splicing ◽

Rna Binding ◽

Rna Binding Proteins ◽

Small Body ◽

Splicing Factor ◽

Nuclear Retention ◽

Ciliary Ultrastructure ◽

Retention Signal

AbstractShuttling RNA-binding proteins coordinate nuclear and cytoplasmic steps of gene expression. The SR family proteins regulate RNA splicing in the nucleus and a subset of them, including SRSF1, shuttles between the nucleus and cytoplasm affecting post-splicing processes. However, the physiological significance of this remains unclear. Here, we used genome editing to knock-in a nuclear retention signal (NRS) in Srsf1 to create a mouse model harboring an SRSF1 protein that is retained exclusively in the nucleus. Srsf1NRS/NRS mutants displayed small body size, hydrocephalus and immotile sperm, all traits associated with ciliary defects. We observed reduced translation of a subset of mRNAs and decreased abundance of proteins involved in multiciliogenesis, with disruption of ciliary ultrastructure and motility in cells derived from this mouse model. These results demonstrate that SRSF1 shuttling is used to reprogram gene expression networks in the context of high cellular demands, as observed here, during motile ciliogenesis.

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SAM68: Signal Transduction and RNA Metabolism in Human Cancer

BioMed Research International ◽

10.1155/2015/528954 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 42

Author(s):

Paola Frisone ◽

Davide Pradella ◽

Anna Di Matteo ◽

Elisa Belloni ◽

Claudia Ghigna ◽

...

Keyword(s):

Cell Cycle ◽

Signal Transduction ◽

Nuclear Export ◽

Cell Biology ◽

Rna Binding ◽

Rna Binding Proteins ◽

Splice Variants ◽

Human Cancer ◽

Rna Metabolism ◽

Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

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Roles of Organellar RNA-Binding Proteins in Plant Growth, Development, and Abiotic Stress Responses

International Journal of Molecular Sciences ◽

10.3390/ijms21124548 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4548 ◽

Cited By ~ 1

Author(s):

Kwanuk Lee ◽

Hunseung Kang

Keyword(s):

Abiotic Stress ◽

Plant Growth ◽

Stress Responses ◽

Translational Control ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Functional Roles ◽

Growth Development

Organellar gene expression (OGE) in chloroplasts and mitochondria is primarily modulated at post-transcriptional levels, including RNA processing, intron splicing, RNA stability, editing, and translational control. Nucleus-encoded Chloroplast or Mitochondrial RNA-Binding Proteins (nCMRBPs) are key regulatory factors that are crucial for the fine-tuned regulation of post-transcriptional RNA metabolism in organelles. Although the functional roles of nCMRBPs have been studied in plants, their cellular and physiological functions remain largely unknown. Nevertheless, existing studies that have characterized the functions of nCMRBP families, such as chloroplast ribosome maturation and splicing domain (CRM) proteins, pentatricopeptide repeat (PPR) proteins, DEAD-Box RNA helicase (DBRH) proteins, and S1-domain containing proteins (SDPs), have begun to shed light on the role of nCMRBPs in plant growth, development, and stress responses. Here, we review the latest research developments regarding the functional roles of organellar RBPs in RNA metabolism during growth, development, and abiotic stress responses in plants.

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