RNA Biology最新文献

The m⁶A 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 m⁶A 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 Arabidopsis thaliana IDRs are important for the functional specialization among the different YTH proteins, known as Evolutionarily Conserved C-Terminal region, ECT 1 to 12. Here by studying the ECT2 protein and using an in vitro biochemical characterization, we show that full-length ECT2 and its YTH domain alone have a distinct ability to bind m⁶A, 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 m⁶A-methylated RNA. Furthermore, we show that the selectivity of ECT2 binding for m⁶A is enhanced by a high uridine content within its neighbouring sequence, where ECT2 N-terminal IDR is believed to contact the target RNA in vivo. 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 m⁶A-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.

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.

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.

SRP9/SRP14 is a protein heterodimer that plays a critical role in the signal recognition particle through its interaction with the scaffolding signal recognition particle RNA (7SL). SRP9/SRP14 binding to 7SL is mediated through a conserved structural motif that is shared with the primate-specific Alu RNA. Alu RNA are transcription products of Alu elements, a retroelement that comprises ~10% of the human genome. Alu RNA are involved in myriad biological processes and are dysregulated in several human disease states. This review focuses on the roles SRP9/SRP14 has in regulating Alu RNA diversification, maturation, and function. The diverse mechanisms through which SRP9/SRP14 regulates Alu RNA exemplify the breadth of protein-mediated regulation of non-coding RNA.

Extracellular vesicles (EVs) are membrane-bound particles released by cells that play vital roles in intercellular communication by transporting diverse biologically active molecules, including RNA molecules, including mRNA, miRNA, lncRNA, and other regulatory RNAs. These RNA types are protected within the lipid bilayer of EVs, ensuring their stability and enabling long-distance cellular interactions. Notably, EVs play roles in infection, where pathogens and host cells use EV-mediated RNA transfer to influence immune responses and disease outcomes. For example, bacterial EVs play a crucial role in infection by modulating host immune responses and facilitating pathogen invasion. This review explores the complex interactions between EV-associated RNA and host-pathogen dynamics in bacteria, parasites, and fungi, aiming to uncover molecular mechanisms in infectious diseases and potential therapeutic targets.

Throughout the tree of life RNA-binding proteins play important roles, but they are poorly characterized in cyanobacteria. Overexpression of the predicted RNA-binding protein Ssr1238 in the cyanobacterium Synechocystis 6803 for 24 h led to higher levels of RNase P RNA, tRNAs, and stress-related mRNAs. Co-immunoprecipitation of proteins followed by MS analysis and sequencing of UV crosslinked, co-immunoprecipitated RNA samples identified potential interaction partners of Ssr1238. The most enriched transcript was RNase P RNA, and RnpA, the protein component of RNase P, was among the most highly enriched proteins. A second highly enriched transcript is derived from gene ssl3177, which encodes a central enzyme in cell wall remodelling during cell division. The data also showed a strong connection to the RNA maturation and modification system indicated by co-precipitation of RNA modifying enzymes, riboendonuclease E and enolase. Surprisingly, cyanophycin synthetase and urease were highly enriched as well. In conclusion, Ssr1238 specifically binds to two different transcripts and could be involved in the coordination of RNA maturation, translation, cell division, and aspects of nitrogen metabolism. Our results are consistent with recent findings that the B. subtilis YlxR protein functions as an RNase P modulator (RnpM), extending its proposed role to the phylum cyanobacteria, and suggesting additional functionalities.

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

Although circular RNAs (circRNAs) play important roles in regulating gene expression, the understanding of circRNAs in livestock animals is scarce due to the significant challenge to characterize them from a biological sample. In this study, we assessed the outcomes of bovine circRNA identification using six enrichment approaches with the combination of ribosomal RNAs removal (Ribo); linear RNAs degradation (R); linear RNAs and RNAs with structured 3' ends degradation (RTP); ribosomal RNAs coupled with linear RNAs elimination (Ribo-R); ribosomal RNA, linear RNAs and RNAs with poly (A) tailing elimination (Ribo-RP); and ribosomal RNA, linear RNAs and RNAs with structured 3' ends elimination (Ribo-RTP), respectively. RNA-sequencing analysis revealed that different approaches led to varied ratio of uniquely mapped reads, false-positive rate of identifying circRNAs, and the number of circRNAs per million clean reads (P_adj <0.05). Out of 2,285 and 2,939 highly confident circRNAs identified in liver and rumen tissues, respectively, 308 and 260 were commonly identified from five methods, with Ribo-RTP method identified the highest number of circRNAs. Besides, 507 of 4,051 identified bovine highly confident circRNAs had shared splicing sites with human circRNAs. The findings from this work provide optimized methods to identify bovine circRNAs from cattle tissues for downstream research of their biological roles in cattle.

Ribosomes are large macromolecular complexes composed of both proteins and RNA, that require a plethora of factors and post-transcriptional modifications for their biogenesis. In human mitochondria, the ribosomal RNA is post-transcriptionally modified at ten sites. The N4-methylcytidine (m⁴C) methyltransferase, METTL15, modifies the 12S rRNA of the small subunit at position C1486. The enzyme is essential for mitochondrial protein synthesis and assembly of the mitoribosome small subunit, as shown here and by previous studies. Here, we demonstrate that the m⁴C modification is not required for small subunit biogenesis, indicating that the chaperone-like activity of the METTL15 protein itself is an essential component for mitoribosome biogenesis.

One of the most recent advances in the analysis of viral RNA-cellular protein interactions is the Comprehensive Identification of RNA-binding Proteins by Mass Spectrometry (ChIRP-MS). Here, we used ChIRP-MS in mock-infected and Zika-infected wild-type cells and cells knockout for the zinc finger CCCH-type antiviral protein 1 (ZAP). We characterized 'ZAP-independent' and 'ZAP-dependent' cellular protein interactomes associated with flavivirus RNA and found that ZAP affects cellular proteins associated with Zika virus RNA. The ZAP-dependent interactome identified with ChIRP-MS provides potential ZAP co-factors for antiviral activity against Zika virus and possibly other viruses. Identifying the full spectrum of ZAP co-factors and mechanisms of how they act will be critical to understanding the ZAP antiviral system and may contribute to the development of antivirals.