RNA BiologyPub Date : 2025-12-01Epub Date: 2025-05-30DOI: 10.1080/15476286.2025.2512610
Jiyoon Chung, Yerim Lee, Jimin Yoon, Yoosik Kim
{"title":"Deciphering the multifaceted role of double-stranded RNA sensor protein kinase R: pathophysiological function beyond the antiviral response.","authors":"Jiyoon Chung, Yerim Lee, Jimin Yoon, Yoosik Kim","doi":"10.1080/15476286.2025.2512610","DOIUrl":"10.1080/15476286.2025.2512610","url":null,"abstract":"<p><p>Protein kinase R (PKR) is a serine/threonine kinase that recognizes double-stranded RNAs (dsRNAs) to initiate innate immune signalling during viral infection. PKR dimerizes on long dsRNAs and undergoes autophosphorylation. Phosphorylated/Activated PKR then catalyses the phosphorylation of numerous substrates to control global translation, inflammatory response, and cell signalling pathways. While primarily known for its antiviral role, emerging evidence suggests that PKR can play multifaceted roles in uninfected cells by interacting with cellular dsRNAs and protein regulators. The misactivation of PKR in uninfected cells is associated with many degenerative and inflammatory diseases. Even in healthy cells, PKR can affect gene expression by controlling mRNA splicing and gene-specific translation under stress. In addition, PKR can modulate cell cycle progression and promote cellular differentiation in several tissue types. This review explores PKR function in various pathological and physiological contexts in the absence of viral stimuli. By elucidating these diverse functions, we aim to highlight the perspectives in cellular dsRNA research and the therapeutic implications of targeting PKR, stimulating further research into this versatile and essential RNA-dependent kinase.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":"22 1","pages":"1-14"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-06-29DOI: 10.1080/15476286.2025.2506712
Christian Ramirez, Elena Perenthaler, Fabio Lauria, Toma Tebaldi, Gabriella Viero
{"title":"Computational limitations and future needs to unravel the full potential of 2'-O-methylation and C/D box snoRNAs.","authors":"Christian Ramirez, Elena Perenthaler, Fabio Lauria, Toma Tebaldi, Gabriella Viero","doi":"10.1080/15476286.2025.2506712","DOIUrl":"10.1080/15476286.2025.2506712","url":null,"abstract":"<p><p>This review evaluates the current state of C/D snoRNA databases and prediction tools in relation to 2'-O-methylation (2'-O-Me). It highlights the limitations of existing resources in accurately annotating and predicting guide snoRNAs, particularly for newly identified 2'-O-Me sites. We emphasize the need for advanced computational approaches specifically tailored to 2'-O-Me to enable the discovery and functional analysis of snoRNAs. Given the growing importance of 2'-O-Me in areas such as cancer epitranscriptomics, ribosome biogenesis, and heterogeneity, existing tools remain inadequate. As 2'-O-Me gains recognition as a potential biomarker and therapeutic target, more sophisticated methods are urgently needed to improve snoRNA annotation and prediction, facilitating biomedical advancements.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-11"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-03-24DOI: 10.1080/15476286.2025.2483484
Laura Contreras, Alfonso Rodríguez-Gil, Jordi Muntané, Jesús de la Cruz
{"title":"Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells.","authors":"Laura Contreras, Alfonso Rodríguez-Gil, Jordi Muntané, Jesús de la Cruz","doi":"10.1080/15476286.2025.2483484","DOIUrl":"10.1080/15476286.2025.2483484","url":null,"abstract":"<p><p>Sorafenib (Sfb) is a multikinase inhibitor regularly used for the management of patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned, which strongly correlates with the presence of established mRNA <i>cis</i>-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provides valuable information that can facilitate the analysis of other drugs for the development of novel combined treatment strategies based on Sfb therapy.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-11"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-08-29DOI: 10.1080/15476286.2025.2551299
Yatzu Chiu, Risa Ishida, Yohsuke Moriyama, Jan Grašič, Keiko Kono
{"title":"Time-resolved miRNA-mRNA integrated analysis reveals the miRNA-mRNA networks underlying plasma membrane damage-dependent senescence and DNA damage response-dependent senescence in WI-38 normal human fibroblasts.","authors":"Yatzu Chiu, Risa Ishida, Yohsuke Moriyama, Jan Grašič, Keiko Kono","doi":"10.1080/15476286.2025.2551299","DOIUrl":"10.1080/15476286.2025.2551299","url":null,"abstract":"<p><p>Cellular senescence is a stable cell cycle arrest associated with upregulated inflammatory responses. Senescent cells contribute to various pathological and physiological processes including organismal ageing and cancer. Cellular senescence can be induced by various cellular stresses including DNA damage, telomere shortening, oncogene activation, and epigenetic alterations. We have shown that plasma membrane damage can also induce cellular senescence. However, common and specific molecular mechanisms among different senescent cell subtypes remain unknown. MicroRNAs (miRNAs) regulate mRNA and rewire gene expression profiles, contributing to multiple processes including cellular senescence. Here, we performed time-resolved miRNA sequencing and compared the results with mRNA sequencing results using cells experiencing plasma membrane damage-dependent senescence (PMD-Sen) and cells undergoing DNA damage response-dependent senescence (DDR-Sen). We found 65 miRNAs that are differentially regulated in PMD-Sen, contributing to 2,495 miRNA-mRNA pairs. Moreover, PMD-Sen and DDR-Sen shared 41 miRNAs across their sets of miRNA-mRNA pairs. Notably, miR-155-5p emerged as the miRNA with the largest number of shared miRNA-mRNA pairs that exhibit a highly negative correlation. These results highlight miR-155-5p as the potential key regulator of PMD-Sen and DDR-Sen.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":"22 1","pages":"1-19"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144967063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-09-15DOI: 10.1080/15476286.2025.2558631
Yukyeong Lee, Camilla Boschian, Kinarm Ko
{"title":"MicroRNA-mediated regulation of proliferation, lineage differentiation, and apoptosis in neural stem cells.","authors":"Yukyeong Lee, Camilla Boschian, Kinarm Ko","doi":"10.1080/15476286.2025.2558631","DOIUrl":"10.1080/15476286.2025.2558631","url":null,"abstract":"<p><p>Neural stem cells (NSCs) are multipotent stem cells with self-renewal capacity, able to differentiate into all neural lineages of the central nervous system, including neurons, oligodendrocytes, and astrocytes; thus, their proliferation and differentiation are essential for embryonic neurodevelopment and adult brain homoeostasis. Dysregulation in these processes is implicated in neurological disorders, highlighting the need to elucidate how NSCs proliferate and differentiate to clarify the mechanisms of neurogenesis and uncover potential therapeutic targets. MicroRNAs (miRNAs) are small, post-transcriptional regulators of gene expression involved in many aspects of nervous system development and function. Multiple studies have shown that miRNAs control the balance between self-renewal and differentiation during development through transcriptional networks and fine-tuned signalling pathways. They also regulate key biological processes, including cell fate determination, developmental timing, neurogenesis, gliogenesis, and apoptosis. Transcriptomic analyses and high-resolution profiling have revealed temporally and spatially restricted miRNA expression patterns in NSCs and their progeny, suggesting highly context-dependent regulatory functions. Here, we provide an integrated overview of recent advances in miRNA biology relevant to NSC maintenance and lineage specification, with a focus on the mechanistic understanding of miRNA roles in neuronal differentiation, glial development, and programmed cell death across neural development.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-17"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145024147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dual synthesis pathways of scaRNA28 via intronic processing of transformation/transcription domain-associated protein transcripts and a novel independent transcription unit.","authors":"Keiichi Izumikawa, Tatsuya Shida, Hideaki Ishikawa, Sotaro Miyao, Takayuki Ohga, Masato Taoka, Yuko Nobe, Hiroshi Nakayama, Masami Nagahama","doi":"10.1080/15476286.2025.2513133","DOIUrl":"10.1080/15476286.2025.2513133","url":null,"abstract":"<p><p>Small Cajal body-specific RNAs (scaRNAs) are noncoding RNAs involved in the maturation of U-rich small nuclear RNAs. Except for a few that have their own transcription units, most scaRNA genes are embedded in introns and are predicted to be transcribed with host genes. Herein, we report that scaRNA28 is the first scaRNA with a dual synthesis pathway, and that this RNA is transcribed in an independent transcription unit (ITU) by RNA polymerase II while located in intron 2 of the transformation/transcription domain-associated protein (TRRAP) gene. We evaluated the scaRNA28 synthesis pathway using minigenes containing exon 2, intron 2, and exon 3 of <i>TRRAP</i>. A minigene with a mutation preventing 5' splicing recognition of the exon 2/intron 2 junction generated scaRNA28, suggesting a pathway processing unspliced transcripts into scaRNA28. Even promoterless minigenes and DNA fragments with regions from exons 2 to 3 of <i>TRRAP</i> showed RNA polymerase II-dependent synthesis of scaRNA28, indicating a novel synthesis pathway involving an ITU. Linker-scanning mutational analysis revealed that the promoter region required for scaRNA28 expression in the ITU is located within 60 bases including exon 2/intron 2 junction of <i>TRRAP</i>, and especially the first two bases of intron 2 region, a putative part of the MYC-binding (E-box) motif, are essential for scaRNA28 expression in the ITU. MYC promotes scaRNA28 expression by binding to the promoter region in the ITU. Our findings demonstrated a novel transcriptional pathway for the synthesis of scaRNA28, the first scaRNA with a dual synthesis pathway.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-12"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-03-02DOI: 10.1080/15476286.2025.2472448
Nils Peiter, Anna Einert, Pauline Just, Frida Jannasch, Marija Najdovska, Michael Rother
{"title":"Defining the methanogenic SECIS element <i>in vivo</i> by targeted mutagenesis.","authors":"Nils Peiter, Anna Einert, Pauline Just, Frida Jannasch, Marija Najdovska, Michael Rother","doi":"10.1080/15476286.2025.2472448","DOIUrl":"10.1080/15476286.2025.2472448","url":null,"abstract":"<p><p>In all domains of life, Archaea, Eukarya and Bacteria, the unusual amino acid selenocysteine (Sec) is co-translationally incorporated into proteins by recoding a UGA stop codon to a sense codon. A secondary structure on the mRNA, the selenocysteine insertion sequence (SECIS), is required, but its position, secondary structure and binding partner(s) are not conserved across the tree of life. Thus far, the nature of archaeal SECIS elements has been derived mainly from sequence analyses. A recently developed <i>in vivo</i> reporter system was used to study the structure-function relationships of SECIS elements in <i>Methanococcus maripaludis</i>. Through targeted mutagenesis, we defined the minimal functional SECIS element, the parts of the SECIS where structure and not the identity of the bases are relevant for function, and identified two conserved -and invariant- adenines that are most likely to interact with the other factor(s) of the Sec recoding machinery. Finally, we demonstrated the functionality of SECIS elements in the 5`-untranslated region of the mRNA and identified a potential mechanism of SECIS repositioning in the vicinity of the UGA for efficient selenocysteine insertion.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-13"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-04-29DOI: 10.1080/15476286.2025.2498203
Rita Pancsa, Dmitry E Andreev, Kellie Dean
{"title":"The implication of non-AUG-initiated N-terminally extended proteoforms in cancer.","authors":"Rita Pancsa, Dmitry E Andreev, Kellie Dean","doi":"10.1080/15476286.2025.2498203","DOIUrl":"https://doi.org/10.1080/15476286.2025.2498203","url":null,"abstract":"<p><p>Dysregulated translation is a hallmark of cancer, and recent genome-wide studies in tumour cells have uncovered widespread translation of non-canonical reading frames that often initiate at non-AUG codons. If an upstream non-canonical start site is located within a frame with an annotated coding sequence (CDS), such translation events can lead to the production of proteoforms with altered N-termini (PANTs). Certain examples of PANTs from oncogenes (e.g. c-MYC) and tumour suppressors (e.g. PTEN) have been previously linked to cancer. We have performed a systematic computational analysis on recently identified non-AUG initiation-derived N-terminal extensions of cancer-associated proteins, and we discuss how these extended proteoforms may acquire new oncogenic properties. We identified a loss of stability for the N-terminally extended proteoforms of oncogenes TCF-4 and SOX2. Furthermore, we discovered likely functional short linear motifs within the N-terminal extensions of oncogenes and tumour suppressors (SOX2, SUFU, SFPQ, TOP1 and SPEN/SHARP) that could provide an explanation for previously described functionalities or interactions of the proteins. In all, we identify novel cases where PANTs likely show different localization, functions, partner binding or turnover rates compared to the annotated proteoforms. Therefore, we propose that alterations in the stringency of translation initiation, often seen under conditions of cellular stress, may result in reprogramming of translation to generate novel PANTs that influence cancer progression.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":"22 1","pages":"1-18"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle.","authors":"Valeria Famà, Lucia Coscujuela Tarrero, Roberto Albanese, Lorenzo Calviello, Stefano Biffo, Mattia Pelizzola, Mattia Furlan","doi":"10.1080/15476286.2025.2483001","DOIUrl":"10.1080/15476286.2025.2483001","url":null,"abstract":"<p><p>Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as a linear sequence of events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps of gene expression, even when spatially and temporally distant. In this review, we focus on translation, the final stage of gene expression, and examine its coupling with key stages of mRNA metabolism: synthesis, processing, export, and decay. For each of these processes, we provide an overview of known instances of coupling with translation. Furthermore, we discuss the role of high-throughput technologies in uncovering these intricate interactions on a genome-wide scale. Finally, we highlight key challenges and propose future directions to advance our understanding of how coupling mechanisms orchestrate robust and adaptable gene expression programs.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-12"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
RNA BiologyPub Date : 2025-12-01Epub Date: 2025-01-11DOI: 10.1080/15476286.2025.2449775
Martin Hart, Caroline Diener, Stefanie Rheinheimer, Tim Kehl, Andreas Keller, Hans-Peter Lenhof, Eckart Meese
{"title":"Expanding the immune-related targetome of miR-155-5p by integrating time-resolved RNA patterns into miRNA target prediction.","authors":"Martin Hart, Caroline Diener, Stefanie Rheinheimer, Tim Kehl, Andreas Keller, Hans-Peter Lenhof, Eckart Meese","doi":"10.1080/15476286.2025.2449775","DOIUrl":"10.1080/15476286.2025.2449775","url":null,"abstract":"<p><p>The lack of a sufficient number of validated miRNA targets severely hampers the understanding of their biological function. Even for the well-studied miR-155-5p, there are only 239 experimentally validated targets out of 42,554 predicted targets. For a more complete assessment of the immune-related miR-155 targetome, we used an inverse correlation of time-resolved mRNA profiles and miR-155-5p expression of early CD4+ T cell activation to predict immune-related target genes. Using a high-throughput miRNA interaction reporter (HiTmIR) assay we examined 90 target genes and confirmed 80 genes as direct targets of miR-155-5p. Our study increases the current number of verified miR-155-5p targets approximately threefold and exemplifies a method for verifying miRNA targetomes as a prerequisite for the analysis of miRNA-regulated cellular networks.</p>","PeriodicalId":21351,"journal":{"name":"RNA Biology","volume":" ","pages":"1-9"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}