RNA Biol [JOURNAL]
Sun
200 papers
Regulation of magnesium ion transport in : insights into the role of the 5' upstream region in expression.
Vézina Bédard AS, Michaud A, Quenette F … +5 more , Singh N, de Lemos Martins F, Wade JT, Guillier M, Lafontaine DA
RNA Biol · 2024 Jan · PMID 39513341 · Full text
In , transport of magnesium ions across the cellular membrane relies on MgtA and CorA transporters. While the expression of is controlled by the two-component system PhoQ/PhoP and 5' upstream region elements, expressio...
In , transport of magnesium ions across the cellular membrane relies on MgtA and CorA transporters. While the expression of is controlled by the two-component system PhoQ/PhoP and 5' upstream region elements, expression is considered to be constitutive and not to depend on cellular factors. Importantly, the 5' upstream region of is predicted to fold into structures highly similar to the magnesium-sensing 5' upstream region. Here using biochemical and genetic assays, we show that the intracellular concentration of magnesium ions affects expression. Similarly to , we find that the effect of magnesium ions on expression is mediated by the 5' upstream region. We demonstrate that the RNA structure is important for regulation and that the Rho transcription factor is involved in the modulation of transcription termination. Consistent with previous studies, we find that translation of , a short ORF located within the 5' upstream region, is important for regulation. Our data indicate that the efficiency of translation is inversely proportional to expression, similar to what has been described for and in . Using a novel assay to control the import of magnesium ions, we show that while the expression of is regulated by both extra- and intracellular magnesium ions, is regulated by variations in intracellular magnesium ions. Our results support a model in which the expression of is regulated by the 5' upstream region that senses variations of intracellular magnesium ions.
Plant ribosomes as a score to fathom the melody of 2'--methylation across evolution.
Neumann SA, Gaspin C, Sáez-Vásquez J
RNA Biol · 2024 Jan · PMID 39508203 · Full text
2'--ribose methylation (2'--Me) is one of the most common RNA modifications detected in ribosomal RNAs (rRNA) from bacteria to eukaryotic cells. 2'--Me favours a specific RNA conformation and protects RNA from hydrolysis...
2'--ribose methylation (2'--Me) is one of the most common RNA modifications detected in ribosomal RNAs (rRNA) from bacteria to eukaryotic cells. 2'--Me favours a specific RNA conformation and protects RNA from hydrolysis. Moreover, rRNA 2'--Me might stabilize its interactions with messenger RNA (mRNA), transfer RNA (tRNA) or proteins. The extent of rRNA 2'--Me fluctuates between species from 3-4 sites in bacteria to tens of sites in archaea, yeast, algae, plants and human. Depending on the organism as well as the rRNA targeting site and position, the 2'--Me reaction can be carried out by several site-specific RNA methyltransferases (RMTase) or by a single RMTase associated to specific RNA guides. Here, we review current progresses in rRNA 2'--Me (sites/Nm and RMTases) in plants and compare the results with molecular clues from unicellular (bacteria, archaea, algae and yeast) as well as multicellular (human and plants) organisms.
LncRNAs in melanoma phenotypic plasticity: emerging targets for promising therapies.
Beatriz Cristina Biz T, Carolina de Sousa CS, Frank John S … +1 more , Miriam Galvonas J
RNA Biol · 2024 Jan · PMID 39498940 · Full text
Long non-coding RNAs (lncRNAs) have received growing attention due to their diverse regulatory roles in cancer, including in melanoma, an aggressive type of skin cancer. The plasticity and phenotypic adaptability of mela...
Long non-coding RNAs (lncRNAs) have received growing attention due to their diverse regulatory roles in cancer, including in melanoma, an aggressive type of skin cancer. The plasticity and phenotypic adaptability of melanoma cells are crucial factors contributing to therapeutic resistance. The identification of molecules playing key roles in melanoma cell plasticity could unravel novel and more effective therapeutic targets. This review presents current concepts of melanoma cell plasticity, illustrating its fluidity and dismissing the outdated notion of epithelial-mesenchymal-like transition as a simplistic binary process. Emphasis is placed on the pivotal role of lncRNAs in orchestrating cell plasticity, employing various mechanisms recently elucidated and unveiling their potential as promising targets for novel therapeutic strategies. Insights into the molecular mechanisms coordinated by lncRNAs in melanoma pave the way for the development of RNA-based therapies, holding great promise for enhancing treatment outcomes and offering a glimpse into a more effective approach to melanoma treatment.
The role of dsRNA A-to-I editing catalyzed by ADAR family enzymes in the pathogeneses.
Liu W, Wu Y, Zhang T … +3 more , Sun X, Guo D, Yang Z
RNA Biol · 2024 Jan · PMID 39449182 · Full text
The process of adenosine deaminase (ADAR)-catalyzed double-stranded RNA (dsRNA) Adenosine-to-Inosine (A-to-I) editing is essential for the correction of pathogenic mutagenesis, as well as the regulation of gene expressio...
The process of adenosine deaminase (ADAR)-catalyzed double-stranded RNA (dsRNA) Adenosine-to-Inosine (A-to-I) editing is essential for the correction of pathogenic mutagenesis, as well as the regulation of gene expression and protein function in mammals. The significance of dsRNA A-to-I editing in disease development and occurrence is explored using inferential statistics and cluster analyses to investigate the enzymes involved in dsRNA editing that can catalyze editing sites across multiple biomarkers. This editing process, which occurs in coding or non-coding regions, has the potential to activate abnormal signalling pathways that contributes to disease pathogenesis. Notably, the ADAR family enzymes play a crucial role in initiating the editing process. ADAR1 is upregulated in most diseases as an oncogene during tumorigenesis, whereas ADAR2 typically acts as a tumour suppressor. Furthermore, this review also provides an overview of small molecular inhibitors that disrupt the expression of ADAR enzymes. These inhibitors not only counteract tumorigenicity but also alleviate autoimmune disorders, neurological neurodegenerative symptoms, and metabolic diseases associated with aberrant dsRNA A-to-I editing processes. In summary, this comprehensive review offers detailed insights into the involvement of dsRNA A-to-I editing in disease pathogenesis and highlights the potential therapeutic roles for related small molecular inhibitors. These scientific findings will undoubtedly contribute to the advancement of personalized medicine based on dsRNA A-to-I editing.
Regulation and mechanisms of action of RNA helicases.
Lang N, Jagtap PKA, Hennig J
RNA Biol · 2024 Jan · PMID 39435974 · Full text
RNA helicases are an evolutionary conserved class of nucleoside triphosphate dependent enzymes found in all kingdoms of life. Their cellular functions range from transcription regulation up to maintaining genomic stabili...
RNA helicases are an evolutionary conserved class of nucleoside triphosphate dependent enzymes found in all kingdoms of life. Their cellular functions range from transcription regulation up to maintaining genomic stability and viral defence. As dysregulation of RNA helicases has been shown to be involved in several cancers and various diseases, RNA helicases are potential therapeutic targets. However, for selective targeting of a specific RNA helicase, it is crucial to develop a detailed understanding about its dynamics and regulation on a molecular and structural level. Deciphering unique features of specific RNA helicases is of fundamental importance not only for future drug development but also to deepen our understanding of RNA helicase regulation and function in cellular processes. In this review, we discuss recent insights into regulation mechanisms of RNA helicases and highlight models which demonstrate the interplay between helicase structure and their functions.
Identification and functional characterization of lncRNAs involved in human monocyte-to-macrophage differentiation.
Montano C, Covarrubias S, Malekos E … +2 more , Katzman S, Carpenter S
RNA Biol · 2024 Jan · PMID 39429195 · Full text
Although long noncoding RNAs (lncRNAs) constitute the majority of the human transcriptome, the functional roles of most remain elusive. While protein-coding genes in macrophage biology have been extensively studied, the...
Although long noncoding RNAs (lncRNAs) constitute the majority of the human transcriptome, the functional roles of most remain elusive. While protein-coding genes in macrophage biology have been extensively studied, the contribution of lncRNAs in this context is poorly understood. Given the vast number of lncRNAs (>20,000), identifying candidates for functional characterization poses a significant challenge. Here, we present two complementary approaches to pinpoint and investigate lncRNAs involved in monocyte-to-macrophage differentiation: RNA-seq for functional inference and a high-throughput functional screen. These strategies enabled us to identify four lncRNA regulators of monocyte differentiation: , , , and . Preliminary insights suggest these lncRNAs may act in through neighbouring protein-coding genes, although their precise mechanisms remain to be elucidated. We further discuss the strengths and weaknesses of these methodologies, along with validation pipelines crucial for establishing lncRNA functionality.
Retrotransposon life cycle and its impacts on cellular responses.
Luqman-Fatah A, Nishimori K, Amano S … +2 more , Fumoto Y, Miyoshi T
RNA Biol · 2024 Jan · PMID 39396200 · Full text
Approximately 45% of the human genome is comprised of transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are parti...
Approximately 45% of the human genome is comprised of transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are particularly abundant, and some of the copies are still capable of mobilization within the genome through RNA intermediates. This review focuses on the life cycle of human retrotransposons and summarizes their regulatory mechanisms and impacts on cellular processes. Retrotransposons are generally epigenetically silenced in somatic cells, but are transcriptionally reactivated under certain conditions, such as tumorigenesis, development, stress, and ageing, potentially leading to genetic instability. We explored the dual nature of retrotransposons as genomic parasites and regulatory elements, focusing on their roles in genetic diversity and innate immunity. Furthermore, we discuss how host factors regulate retrotransposon RNA and cDNA intermediates through their binding, modification, and degradation. The interplay between retrotransposons and the host machinery provides insight into the complex regulation of retrotransposons and the potential for retrotransposon dysregulation to cause aberrant responses leading to inflammation and autoimmune diseases.
Rbm3 deficiency leads to transcriptome-wide splicing alterations.
Erkelenz S, Grzonka M, Papadakis A … +3 more , Schaal H, Hoeijmakers JHJ, Gyenis Á
RNA Biol · 2024 Jan · PMID 39387568 · Full text
(RNA-binding motif protein 3) is a stress responsive gene, which maintains cellular homeostasis and promotes survival upon various harmful cellular stimuli. Rbm3 protein shows conserved structural and molecular similarit...
(RNA-binding motif protein 3) is a stress responsive gene, which maintains cellular homeostasis and promotes survival upon various harmful cellular stimuli. Rbm3 protein shows conserved structural and molecular similarities to heterogeneous nuclear ribonucleoproteins (hnRNPs), which regulate all steps of the mRNA metabolism. Growing evidence is pointing towards a broader role of Rbm3 in various steps of gene expression. Here, we demonstrate that Rbm3 deficiency is linked to transcriptome-wide pre-mRNA splicing alterations, which can be reversed through Rbm3 co-expression from a cDNA. Using an MS2 tethering assay, we show that Rbm3 regulates splice site selection similar to other hnRNP proteins when recruited between two competing 5 splice sites. Furthermore, we show that the N-terminal part of Rbm3 encompassing the RNA recognition motif (RRM), is sufficient to elicit changes in splice site selection. On the basis of these findings, we propose a novel, undescribed function of Rbm3 in RNA splicing that contributes to the preservation of transcriptome integrity.
Estrogen receptor alpha (ERα) regulates PARN-mediated nuclear deadenylation and gene expression in breast cancer cells.
Varriano S, Yu A, Xu YQ … +3 more , Natelson DM, Ramadei A, Kleiman FE
RNA Biol · 2024 Jan · PMID 39392174 · Full text
The estrogen signalling pathway is highly dynamic and primarily mediated by estrogen receptors (ERs) that transcriptionally regulate the expression of target genes. While transcriptional functions of ERs have been widely...
The estrogen signalling pathway is highly dynamic and primarily mediated by estrogen receptors (ERs) that transcriptionally regulate the expression of target genes. While transcriptional functions of ERs have been widely studied, their roles in RNA biology have not been extensively explored. Here, we reveal a novel biological role of ER alpha (ERα) in mRNA 3' end processing in breast cancer cells, providing an alternative mechanism in regulating gene expression at the post-transcriptional level. We show that ERα activates poly(A) specific ribonuclease (PARN) deadenylase using assays, and that this activation is further increased by tumour suppressor p53, a factor involved in mRNA processing. Consistent with this, we confirm ERα-mediated activation of nuclear deadenylation by PARN in samples from MCF7 and T47D breast cancer cells that vary in expression of ERα and p53. We further show that ERα can form complex(es) with PARN and p53. Lastly, we identify and validate expression of common mRNA targets of ERα and PARN known to be involved in cell invasion, metastasis and angiogenesis, supporting the functional overlap of these factors in regulating gene expression in a transactivation-independent manner. Together, these results show a new regulatory mechanism by which ERα regulates mRNA processing and gene expression post-transcriptionally, highlighting its contribution to unique transcriptomic profiles and breast cancer progression.
Mitochondrial RNA maturation.
Chrzanowska-Lightowlers ZM, Lightowlers RN
RNA Biol · 2024 Jan · PMID 39385590 · Full text
The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples....
The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.
Correction.
RNA Biol · 2024 Jan · PMID 39381964 · Full text
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Representation of non-coding RNA-mediated regulation of gene expression using the Gene Ontology.
Antonazzo G, Gaudet P, Lovering RC … +1 more , Attrill H
RNA Biol · 2024 Jan · PMID 39374113 · Full text
Regulatory non-coding RNAs (ncRNAs) are increasingly recognized as integral to the control of biological processes. This is often through the targeted regulation of mRNA expression, but this is by no means the only mecha...
Regulatory non-coding RNAs (ncRNAs) are increasingly recognized as integral to the control of biological processes. This is often through the targeted regulation of mRNA expression, but this is by no means the only mechanism through which regulatory ncRNAs act. The Gene Ontology (GO) has long been used for the systematic annotation of protein-coding and ncRNA gene function, but rapid progress in the understanding of ncRNAs meant that the ontology needed to be revised to accurately reflect current knowledge. Here, a targeted effort to revise GO terms used for the annotation of regulatory ncRNAs is described, focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), small interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs). This paper provides guidance to biocurators annotating ncRNA-mediated processes using the GO and serves as background for researchers wishing to make use of the GO in their studies of ncRNAs and the biological processes they regulate.
Role of RNA polymerase III transcription and regulation in ischaemic stroke.
Tsang CK, Zheng XFS
RNA Biol · 2024 Jan · PMID 39363536 · Full text
Ischaemic stroke is a leading cause of death and life-long disability due to neuronal cell death resulting from interruption of glucose and oxygen supplies. RNA polymerase III (Pol III)-dependent transcription plays a ce...
Ischaemic stroke is a leading cause of death and life-long disability due to neuronal cell death resulting from interruption of glucose and oxygen supplies. RNA polymerase III (Pol III)-dependent transcription plays a central role in protein synthesis that is necessary for normal cerebral neuronal functions, and the survival and recovery under pathological conditions. Notably, Pol III transcription is highly sensitive to ischaemic stress that is known to rapidly shut down Pol III transcriptional activity. However, its precise role in ischaemic stroke, especially during the acute and recovery phases, remains poorly understood. The microenvironment within the ischaemic brain undergoes dynamic changes in different phases after stroke. Emerging evidence highlights the distinct roles of Pol III transcription in neuroprotection during the acute phase and repair during the recovery phase of stroke. Additionally, investigations into the mTOR-MAF1 signalling pathway, a conserved regulator of Pol-III transcription, reveal its therapeutic potential in enhancing acute phase neuroprotection and recovery phase repair.
Origin & influence of autocatalytic reaction networks at the advent of the RNA world.
Zorc SA, Roy RN
RNA Biol · 2024 Jan · PMID 39358873 · Full text
Research on the origin of life investigates the transition from abiotic chemistry to the emergence of biology, with the 'RNA world hypothesis' as the leading theory. RNA's dual role in storage and catalysis suggests its...
Research on the origin of life investigates the transition from abiotic chemistry to the emergence of biology, with the 'RNA world hypothesis' as the leading theory. RNA's dual role in storage and catalysis suggests its importance in this narrative. The discovery of natural ribozymes emphasizes RNA's catalytic capabilities in prebiotic environments, supporting the plausibility of an RNA world and prompting exploration of precellular evolution. Collective autocatalytic sets (CASs) mark a crucial milestone in this transition, fostering complexity through autocatalysis. While modern biology emphasizes sequence-specific polymerases, remnants of CASs persist in primary metabolism highlighting their significance. Autocatalysis, driven by CASs, promotes complexity through mutually interdependent catalytic sets. Yet, the transition from ribonucleotides to complex RNA oligomers remains puzzling. Questions persist about the genesis of the first self-replicating RNA molecule, RNA's stability in prebiotic conditions, and the shift to complex molecular reproduction. This review delves into diverse facets of the RNA world's emergence, addressing critical bottlenecks and scientific advances. Integrating insights from simulation and in vitro evolution research, we illuminate the multistep biogenesis of catalytic RNA from the abiotic world. Through this exploration, we aim to elucidate the journey from the primordial soup to the dawn of life, emphasizing the interplay between chemistry and biology in understanding life's origins.
m6A modification of RNA in cervical cancer: role and clinical perspectives.
Gao Y, Guo Q, Yu L
RNA Biol · 2024 Jan · PMID 39344658 · Full text
N6-methyladenosine (m6A) is widely recognized as the predominant form of RNA modification in higher organisms, with the capability to finely regulate RNA metabolism, thereby influencing a series of crucial physiological...
N6-methyladenosine (m6A) is widely recognized as the predominant form of RNA modification in higher organisms, with the capability to finely regulate RNA metabolism, thereby influencing a series of crucial physiological and pathological processes. These processes include regulation of gene expression, cell proliferation, invasion and metastasis, cell cycle control, programmed cell death, interactions within the tumour microenvironment, energy metabolism, and immune regulation. With advancing research into the mechanisms of RNA methylation, the pivotal role of m6A modification in the pathophysiology of reproductive system tumours, particularly cervical cancer, has been progressively unveiled. This discovery has opened new research avenues and presented significant potential for the diagnosis, prognostic evaluation, and treatment of diseases. This review delves deeply into the biological functions of m6A modification and its mechanisms of action in the onset and progression of cervical cancer. Furthermore, it explores the prospects of m6A modification in the precision diagnosis and treatment of cervical cancer, aiming to provide new perspectives and a theoretical basis for innovative and advanced treatment strategies for cervical cancer.
Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with .
Sais D, Chowdhury S, Dalton JP … +2 more , Tran N, Donnelly S
RNA Biol · 2024 Jan · PMID 39344634 · Full text
Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host's immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the a...
Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host's immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with . We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.
alternative polyadenylation is dependent on stochastic poly(a) site usage and splicing efficiencies.
Liu L, Seimiya T, Manley JL
RNA Biol · 2024 Jan · PMID 39327832 · Full text
Transcripts from the human gene, which encodes a central component of the mRNA polyadenylation (PA) machinery, are subject to alternative polyadenylation (APA) within promoter-proximal introns/exons. This APA, which its...
Transcripts from the human gene, which encodes a central component of the mRNA polyadenylation (PA) machinery, are subject to alternative polyadenylation (APA) within promoter-proximal introns/exons. This APA, which itself involves usage of multiple PA sites, results in the production of two non-canonical protein isoforms, V2 and V3, that are functionally completely unrelated to the full-length protein, with roles in innate immunity. The mechanism and regulation of APA are unclear. Here, we report that levels of the PA factor CFIm25 modulate V2 and V3 expression, and that PA site usage of both V2 and V3 varies in distinct immune responses. Using newly developed assays to measure splicing and PA site strength, we show that splicing of V2-associated intron 6 is inefficient, allowing V2 to be produced using weak PA sites. Usage of V3's strong PA sites, on the other hand, is relatively low, reflecting the high efficiency of intron 7 splicing coupled with dependency on usage of an alternative 3' splice site within the intron. Overall, our findings demonstrate that usage of alternative PA sites is stochastic, dependent on a complex interplay between splicing and PA, and thus provide new insights into mechanisms underlying APA.
Circadian regulation of translation.
Lyu J, Zhuang Y, Lin Y
RNA Biol · 2024 Jan · PMID 39324589 · Full text
Most, if not all organisms exhibit robust rhythmicity of their biological functions, allowing a perpetual adaptation to external clues within the daily 24 hours-cycle. Studies on circadian rhythm regulation primarily foc...
Most, if not all organisms exhibit robust rhythmicity of their biological functions, allowing a perpetual adaptation to external clues within the daily 24 hours-cycle. Studies on circadian rhythm regulation primarily focused on transcriptional level, considering mRNA levels to represent the primary determinant of oscillations of intracellular protein levels. However, a plethora of emerging evidence suggests that post-transcriptional regulation, particularly rhythmic mRNA translation, is not solely reliant on the oscillation of transcription. Instead, the circadian regulation of mRNA translation plays a critical role as well. A comprehensive understanding of these mechanisms underlying rhythmic translation and its regulation should bridge the gap in rhythm regulation beyond RNA fluctuations in research, and greatly enhance our comprehension of rhythm generation and maintenance. In this review, we summarize the major mechanisms of circadian regulation of translation, including regulation of translation initiation, elongation, and the alteration in rhythmic translation to external stresses, such as endoplasmic reticulum (ER) stress and ageing. We also illuminate the complex interplay between phase separation and mRNA translation. Together, we have summarized various facets of mRNA translation in circadian regulation, to set on forthcoming studies into the intricate regulatory mechanisms underpinning circadian rhythms and their implications for associated disorders.
ECT2 peptide sequences outside the YTH domain regulate its mA-RNA binding.
Seigneurin-Berny D, Karczewski C, Delaforge E … +6 more , Yaacoub K, Gaspar Litholdo C, Favory JJ, Ringkjøbing Jensen M, Bousquet-Antonelli C, Verdel A
RNA Biol · 2024 Jan · PMID 39267376 · Full text
The mA epitranscriptomic mark is the most abundant and widespread internal RNA chemical modification, which through the control of RNA acts as an important factor of eukaryote reproduction, growth, morphogenesis and stre...
The mA epitranscriptomic mark is the most abundant and widespread internal RNA chemical modification, which through the control of RNA acts as an important factor of eukaryote reproduction, growth, morphogenesis and stress response. The main mA readers constitute a super family of proteins with hundreds of members that share a so-called YTH RNA binding domain. The majority of YTH proteins carry no obvious additional domain except for an Intrinsically Disordered Region (IDR). In IDRs are important for the functional specialization among the different YTH proteins, known as Evolutionarily Conserved -Terminal region, ECT 1 to 12. Here by studying the ECT2 protein and using an biochemical characterization, we show that full-length ECT2 and its YTH domain alone have a distinct ability to bind mA, conversely to previously characterized YTH readers. We identify peptide regions outside of ECT2 YTH domain, in the N-terminal IDR, that regulate its binding to mA-methylated RNA. Furthermore, we show that the selectivity of ECT2 binding for mA is enhanced by a high uridine content within its neighbouring sequence, where ECT2 N-terminal IDR is believed to contact the target RNA . Finally, we also identify small structural elements, located next to ECT2 YTH domain and conserved in a large set of YTH proteins, that enhance its binding to mA-methylated RNA. We propose from these findings that some of these regulatory regions are not limited to ECT2 or YTH readers of flowering plants but may be widespread among eukaryotic YTH readers.
A systematic analysis of circRNAs in subnuclear compartments.
Brezski A, Murtagh J, Schulz MH … +1 more , Zarnack K
RNA Biol · 2024 Jan · PMID 39257052 · Full text
CircRNAs are an important class of RNAs with diverse cellular functions in human physiology and disease. A thorough knowledge of circRNAs including their biogenesis and subcellular distribution is important to understand...
CircRNAs are an important class of RNAs with diverse cellular functions in human physiology and disease. A thorough knowledge of circRNAs including their biogenesis and subcellular distribution is important to understand their roles in a wide variety of processes. However, the analysis of circRNAs from total RNA sequencing data remains challenging. Therefore, we developed Calcifer, a versatile workflow for circRNA annotation. Using Calcifer, we analysed APEX-Seq data to compare circRNA occurrence between whole cells, nucleus and subnuclear compartments. We generally find that circRNAs show higher abundance in whole cells compared to nuclear samples, consistent with their accumulation in the cytoplasm. The notable exception is the single-exon circRNA circCANX(9), which is unexpectedly enriched in the nucleus. In addition, we observe that circFIRRE prevails over the linear lncRNA in both the cytoplasm and the nucleus. Zooming in on the subnuclear compartments, we show that circRNAs are strongly depleted from nuclear speckles, indicating that excess splicing factors in this compartment counteract back-splicing. Our results thereby provide valuable insights into the subnuclear distribution of circRNAs. Regarding circRNA function, we surprisingly find that the majority of all detected circRNAs possess complete open reading frames with potential for cap-independent translation. Overall, we show that Calcifer is an easy-to-use, versatile and sustainable workflow for the annotation of circRNAs which expands the repertoire of circRNA tools and allows to gain new insights into circRNA distribution and function.
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