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Simple Summary: Patients with ulcerative colitis (UC) face a higher risk of developing colorectal cancer (CRC) due to chronic inflammation, a known promoter of tumour growth. Here, we review the molecular differences between colitis-associated cancer (CAC) and sporadic CRC, with a focus on "alternative splicing", a mechanism by which the same gene can produce various protein forms. We explore how inflammation triggers changes in this process, increasing cancer risk for UC patients. The revised data emphasize that additional research into these molecular changes could help identify new biomarkers (molecules that indicate disease progression) and pave the way for innovative treatments targeting these alterations. Such advances would improve outcomes and quality of life for patients while contributing to cancer prevention and care. The risk of developing colorectal cancer (CRC) is increased in ulcerative colitis patients compared to the general population. This increased risk results from the state of chronic inflammation, a well-known tumour-promoting condition. This review explores the pathologic and molecular characteristics of colitis-associated colon cancer (CAC), emphasizing the distinct features from sporadic CRC. We focus on the key signalling pathways involved in the transition to CAC, highlighting the emerging role of alternative splicing in these processes, namely on how inflammation-induced alternative splicing can significantly contribute to the increased CRC risk observed among UC patients. This review calls for more transcriptomic studies to elucidate the molecular mechanisms through which inflammation-induced alternative splicing drives CAC pathogenesis. A better understanding of these splicing events is crucial as they may reveal novel biomarkers for disease progression and have the potential to target changes in alternative splicing as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Alternative splicing plays a fundamental role in gene expression and protein complexity. Aberrant splicing impairs cell homeostasis and is closely associated with aging and cellular senescence. Significant changes to alternative splicing, including dysregulated splicing events and the abnormal expression of splicing factors, have been detected during the aging process or in age-related disorders. Here, we highlight the possibility of suppressing aging and cellular senescence by controlling alternative splicing. In this review, we will summarize the latest research progress on alternative splicing in aging and cellular senescence, discuss the roles and regulatory mechanisms of alternative splicing during aging, and then excavate existing and potential approaches to anti-aging by controlling alternative splicing. Novel therapeutic breakthroughs concerning aging and senescence entail a further understanding of regulating alternative splicing mechanically and accurately. [ABSTRACT FROM AUTHOR]

Abstract RNA splicing is a fundamental step of gene expression. While constitutive splicing removes introns and joins exons unbiasedly, alternative splicing (AS) selectively determines the assembly of exons and introns to generate RNA variants corresponding to the same transcript. The biogenesis of circular RNAs (circRNAs) is inextricably associated with AS. Back-splicing, the biogenic process of circRNA, is a special form of AS. In cancer, both AS and circRNA deviate from the original track. In the present review, we delve into the intricate interplay between AS and circRNAs in the context of cancer. The relationship between AS and circRNAs is intricate, where AS modulates the biogenesis of circRNAs and circRNAs in return regulate AS events. Beyond that, epigenetic and posttranscriptional modifications concurrently regulate AS and circRNAs. On the basis of this modality, we summarize current knowledge on how splicing factors and other RNA binding proteins regulate circRNA biogenesis, and how circRNAs interact with splicing factors to influence AS events. Specifically, the feedback loop regulation between circRNAs and AS events contributes greatly to oncogenesis and cancer progression. In summary, resolving the crosstalk between AS and circRNA will not only provide better insight into cancer biology but also provoke novel strategies to combat cancer. Graphical Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early‐diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre‐mRNA processing factor 8 (PRPF8) and RNA‐binding motif protein X‐linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non‐tumor levels and resulted in decreased key tumor‐related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets.

Alternative splicing refers to the process that genes produce RNA isoforms under different splicing modes, and it is an important mechanism for post-transcriptional expression regulation of genes. Alternative splicing has been proved to play an important role in the occurrence and development of cancer, and abnormal splicing is considered as an important symbol of tumor occurrence. Long noncoding RNA (lncRNA) is an important participant and regulator in the process of gene alternative splicing, and many evidences show that lncRNA can affect the occurrence and development of cancer by regulating alternative splicing. In this paper, the research on alternative splicing regulated by lncRNA in cancer is reviewed, and the related bioinformatics tools and databases are summarized. [ABSTRACT FROM AUTHOR]

RNA splicing is a fundamental step of gene expression. While constitutive splicing removes introns and joins exons unbiasedly, alternative splicing (AS) selectively determines the assembly of exons and introns to generate RNA variants corresponding to the same transcript. The biogenesis of circular RNAs (circRNAs) is inextricably associated with AS. Back-splicing, the biogenic process of circRNA, is a special form of AS. In cancer, both AS and circRNA deviate from the original track. In the present review, we delve into the intricate interplay between AS and circRNAs in the context of cancer. The relationship between AS and circRNAs is intricate, where AS modulates the biogenesis of circRNAs and circRNAs in return regulate AS events. Beyond that, epigenetic and posttranscriptional modifications concurrently regulate AS and circRNAs. On the basis of this modality, we summarize current knowledge on how splicing factors and other RNA binding proteins regulate circRNA biogenesis, and how circRNAs interact with splicing factors to influence AS events. Specifically, the feedback loop regulation between circRNAs and AS events contributes greatly to oncogenesis and cancer progression. In summary, resolving the crosstalk between AS and circRNA will not only provide better insight into cancer biology but also provoke novel strategies to combat cancer. [ABSTRACT FROM AUTHOR]

Radiotherapy is a curative arsenal for prostate cancer (PCa), but radioresistance seriously compromises its effectiveness. Dysregulated RNA splicing factors are extensively involved in tumor progression. Nonetheless, the role of splicing factors in radioresistance remains largely unexplored in PCa. Here, 23 splicing factors that are differentially expressed between PCa and adjacent normal tissues across multiple public PCa databases are identified. Among those genes, polypyrimidine tract binding protein 1 (PTBP1) is significantly upregulated in PCa and is positively associated with advanced clinicopathological features and poor prognosis. Gain‐ and loss‐of‐function experiments demonstrate that PTBP1 markedly reinforces genomic DNA stability to desensitize PCa cells to irradiation in vitro and in vivo. Mechanistically, PTBP1 interacts with the heterogeneous nuclear ribonucleoproteins (hnRNP) associated with lethal yellow protein homolog (RALY) and regulates exon 5 splicing of DNA methyltransferase 3b (DNMT3B) from DNMT3B‐S to DNMT3B‐L. Furthermore, upregulation of DNMT3B‐L induces promoter methylation of dual‐specificity phosphatase‐2 (DUSP2) and subsequently inhibits DUSP2 expression, thereby increasing radioresistance in PCa. The findings highlight the role of splicing factors in inducing aberrant splicing events in response to radiotherapy and the potential role of PTBP1 and DNMT3B‐L in reversing radioresistance in PCa. [ABSTRACT FROM AUTHOR]

YB1 (Y box binding protein 1), a multifunctional protein capable of binding to DNA/RNA, is present in most cells and acts as a splicing factor. It is involved in numerous cellular processes such as transcription, translation, and DNA repair, significantly affecting cell proliferation, differentiation, and apoptosis. Abnormal expression of this protein is closely linked to the formation of various malignancies (osteosarcoma, nasopharyngeal carcinoma, breast cancer, etc.). This review examines the multifaceted functions of YB1 and its critical role in osteosarcoma progression, providing new perspectives for potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early‐diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre‐mRNA processing factor 8 (PRPF8) and RNA‐binding motif protein X‐linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non‐tumor levels and resulted in decreased key tumor‐related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract Splicing dysregulation arising from spliceosomal mutations contributes to disease progression and treatment resistance, mostly in hematologic malignancy. Whereas spliceosomal mutations are less common in solid tumors, splicing disorders are pervasive and proven to promote tumorigenesis. However, there is a lack of systematic understanding of the overall splicing dysregulation patterns and how widespread different patterns occur within or across solid tumor lineage. To address these questions, a computational method called SMNPLS (Sparse Multi‐Network Regularized Partial Least Squares) is developed to uncover the pan‐cancer splicing dysregulation landscape by extracting joint modular patterns from paired matrices of splicing factors (SFs) expressions and alternative splicing events (ASEs). Six unique patterns illustrated by ASE‐SF co‐modules are summarized, which involve 1,570 ASEs and altered expression of 170 SFs, covering 40% of TCGA solid tumors. Cross‐cancer commonalities of splicing dysregulation are observed among digestive system neoplasms, renal‐associated tumors, and urogenital tumors. By contrast, brain tumors demonstrate a distinct splicing pattern with the highest ASE‐SF correlation. In addition, some new splicing regulatory relationships are identified that are potentially oncogenic. Overall, the study characterizes the full spectrum of splicing dysregulation patterns, indicating the similarity and specificity of splicing‐derived pathogenesis across 31 human solid tumors.

The progression of spermatogenesis along specific developmental trajectories depends on the coordinated regulation of pre‐mRNA alternative splicing (AS) at the post‐transcriptional level. However, the fundamental mechanism of AS in spermatogenesis remains to be investigated. Here, it is demonstrated that CWF19L2 plays a pivotal role in spermatogenesis and male fertility. In germline conditional Cwf19l2 knockout mice exhibiting male sterility, impaired spermatogenesis characterized by increased apoptosis and decreased differentiated spermatogonia and spermatocytes is observed. That CWF19L2 interacted with several spliceosome proteins to participate in the proper assembly and stability of the spliceosome is discovered. By integrating RNA‐seq and LACE‐seq data, it is further confirmed CWF19L2 directly bound and regulated the splicing of genes related to spermatogenesis (Znhit1, Btrc, and Fbxw7) and RNA splicing (Rbfox1, Celf1, and Rbm10). Additionally, CWF19L2 can indirectly amplify its effect on splicing regulation through modulating RBFOX1. Collectively, this research establishes that CWF19L2 orchestrates a splicing factor network to ensure accurate pre‐mRNA splicing during the early steps of spermatogenesis. [ABSTRACT FROM AUTHOR]

Head and neck malignancies are a significant global health concern, with head and neck squamous cell carcinoma (HNSCC) being the sixth most common cancer worldwide accounting for > 90% of cases. In recent years, there has been growing recognition of the potential role of alternative splicing (AS) in the etiology of cancer. Increasing evidence suggests that AS is associated with various aspects of cancer progression, including tumor occurrence, invasion, metastasis, and drug resistance. Additionally, AS is involved in shaping the tumor microenvironment, which plays a crucial role in tumor development and response to therapy. AS can influence the expression of factors involved in angiogenesis, immune response, and extracellular matrix remodeling, all of which contribute to the formation of a supportive microenvironment for tumor growth. Exploring the mechanism of AS events in HNSCC could provide insights into the development and progression of this cancer, as well as its interaction with the tumor microenvironment. Understanding how AS contributes to the molecular changes in HNSCC cells and influences the tumor microenvironment could lead to the identification of new therapeutic targets. Targeted chemotherapy and immunotherapy strategies tailored to the specific AS patterns in HNSCC could potentially improve treatment outcomes and reduce side effects. This review explores the concept, types, processes, and technological advancements of AS, focusing on its role in the initiation, progression, treatment, and prognosis of HNSCC. [ABSTRACT FROM AUTHOR]

Alternative splicing is a complex gene regulatory process that distinguishes itself from canonical splicing by rearranging the introns and exons of an immature pre-mRNA transcript. This process plays a vital role in enhancing transcriptomic and proteomic diversity from the genome. Alternative splicing has emerged as a pivotal mechanism governing complex biological processes during both heart development and the development of cardiovascular diseases. Multiple alternative splicing factors are involved in a synergistic or antagonistic manner in the regulation of important genes in relevant physiological processes. Notably, circular RNAs have only recently garnered attention for their tissue-specific expression patterns and regulatory functions. This resurgence of interest has prompted a reevaluation of the topic. Here, we provide an overview of our current understanding of alternative splicing mechanisms and the regulatory roles of alternative splicing factors in cardiovascular development and pathological process of different cardiovascular diseases, including cardiomyopathy, myocardial infarction, heart failure and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and Objective: Alternative splicing (AS) offers an important mechanism to form protein polymorphism. A growing body of evidence indicates the correlation between splicing abnormality and carcinoma. Nevertheless, an overall analysis of AS signatures in glioblastoma (GBM) is absent and urgently needed. Methods: TCGA SpliceSea data was used to evaluate the AS profiles and further classified into different AS events. The survival analysis was based on these AS events, and AS-related genes were identified and performed with enrichment analysis. At last, the splicing factor–AS regulatory network was established in Cytoscape. Results: Eight hundred forty-two splicing events were confirmed as prognostic molecular events in GBM. Furthermore, the final prognostic signature constructed by seven AS events gave good result with an area under the curve (AUC) of receiver operating characteristic (ROC) curve up to 0.935 for five years, showing high potency in predicting patients' outcome. We built the splicing regulatory network to show the internal relationship of splicing events in GBM. PC4 and SFRS1 interacting protein 1 (PSIP1) and histone H4 acetylation may play a significant part in the prognosis induced by splicing events. Conclusion: In our study, a high-efficiency prognostic prediction model was built for GBM patients based on AS events, which could become potential prognostic biomarkers for GBM. Meanwhile, PSIP1 may be a critical target for pharmaceutical treatment. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, making it one of the most life‐threatening human cancers. Nevertheless, research on the mechanism of action between alternative splicing (AS) and splicing factor (SF) or biomarkers in GBM is limited. AS is a crucial post‐transcriptional regulatory mechanism. More than 95% of human genes undergo AS events. AS can diversify the expression patterns of genes, thereby increasing the diversity of proteins and playing a significant role in the occurrence and development of tumors. In this study, we downloaded 599 clinical data and 169 transcriptome analysis data from The Cancer Genome Atlas (TCGA) database. Besides, we collected AS data about GBM from TCGA‐SpliceSeq. The overall survival (OS) related AS events in GBM were determined through least absolute shrinkage and selection operator (Lasso) and Cox analysis. Subsequently, the association of these 1825 OS‐related AS events with patient survival was validated using the Kaplan–Meier survival analysis, receiver operating characteristic curve, risk curve analysis, and independent prognostic analysis. Finally, we depicted the AS–SF regulatory network, illustrating the interactions between splicing factors and various AS events in GBM. Additionally, we identified three splicing factors (RNU4‐1, SEC31B, and CLK1) associated with patient survival. In conclusion, based on AS occurrences, we developed a predictive risk model and constructed an interaction network between GBM‐related AS events and SFs, aiming to shed light on the underlying mechanisms of GBM pathogenesis and progression. [ABSTRACT FROM AUTHOR]

YB1 (Y box binding protein 1), a multifunctional protein capable of binding to DNA/RNA, is present in most cells and acts as a splicing factor. It is involved in numerous cellular processes such as transcription, translation, and DNA repair, significantly affecting cell proliferation, differentiation, and apoptosis. Abnormal expression of this protein is closely linked to the formation of various malignancies (osteosarcoma, nasopharyngeal carcinoma, breast cancer, etc.). This review examines the multifaceted functions of YB1 and its critical role in osteosarcoma progression, providing new perspectives for potential therapeutic strategies.

Epithelial to mesenchymal transition (EMT) is a physiological process during development where epithelial cells transform to acquire mesenchymal characteristics, which allows them to migrate and colonize secondary tissues. Many cellular signaling pathways and master transcriptional factors exert a myriad of controls to fine tune this vital process to meet various developmental and physiological needs. Adding to the complexity of this network are post-transcriptional and post-translational regulations. Among them, alternative splicing has been shown to play important roles to drive EMT-associated phenotypic changes, including actin cytoskeleton remodeling, cell-cell junction changes, cell motility and invasiveness. In advanced cancers, transforming growth factor-β (TGF-β) is a major inducer of EMT and is associated with tumor cell metastasis, cancer stem cell self-renewal, and drug resistance. This review aims to provide an overview of recent discoveries regarding alternative splicing events and the involvement of splicing factors in the EMT and TGF-β signaling. It will emphasize the importance of various splicing factors involved in EMT and explore their regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Summary: Most splicing factors are extensively phosphorylated but their physiological functions in plant salt resistance are still elusive.We found that phosphorylation by SnRK1 kinase is essential for SRRM1L nuclear speckle formation and its splicing factor activity in plant cells. In Arabidopsis, loss‐of‐function of SRRM1L leads to the occurrence of alternative pre‐mRNA splicing events and compromises plant resistance to salt stress.In Arabidopsis srrm1l mutant line, we identified an intron‐retention Nuclear factor Y subunit A 10 (NFYA10) mRNA variant by RNA‐Seq and found phosphorylation‐dependent RNA‐binding of SRRM1L is indispensable for its alternative splicing activity. In the wild‐type Arabidopsis, salt stress can activate SnRK1 to phosphorylate SRRM1L, triggering enrichment of functional NFYA10.1 variant to enhance plant salt resistance. By contrast, the Arabidopsis srrm1l mutant accumulates nonfunctional NFYA10.3 variant, sensitizing plants to salt stress.In summary, this work deciphered the molecular mechanisms and physiological functions of SnRK1‐SRRM1L‐NFYA10 module, shedding light on a regulatory pathway to fine‐tune plant adaptation to abiotic stress at the post‐transcriptional and post‐translational levels. [ABSTRACT FROM AUTHOR]

Objective: Ubiquitin-specific peptidase 39 (USP39) plays a carcinogenic role in many cancers, but little research has been conducted examining whether it is involved in head and neck squamous cell carcinoma (HNSCC). Therefore, this study explored the functional role of USP39 in HNSCC. Method: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify differentially expressed proteins (DEPs) between the HNSCC tumor and adjacent healthy tissues. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the functional enrichment of DEPs. Immunohistochemistry was used to detect protein expression. The viability and migration of two HNSCC cell lines, namely CAL27 and SCC25, were detected using the cell counting kit-8 assay and a wound healing assay, respectively. Quantitative real-time PCR was used to detect the expression level of signal transducer and activator of transcription 1 (STAT1) mRNA. Results: LC-MS/MS results identified 590 DEPs between HNSCC and adjacent tissues collected from 4 patients. Through GO and KEGG pathway analyses, 34 different proteins were found to be enriched in the spliceosome pathway. The expression levels of USP39 and STAT1 were significantly higher in HNSCC tumor tissue than in adjacent healthy tissue as assessed by LC-MS/MS analysis, and the increased expression of USP39 and STAT1 protein was confirmed by immunohistochemistry in clinical samples collected from 7 additional patients with HNSCC. Knockdown of USP39 or STAT1 inhibited the viability and migration of CAL27 and SCC25 cells. In addition, USP39 knockdown inhibited the expression of STAT1 mRNA in these cells. Conclusion: Our findings indicated that USP39 knockdown may inhibit HNSCC viability and migration by suppressing STAT1 expression. The results of this study suggest that USP39 may be a potential new target for HNSCC clinical therapy or a new biomarker for HNSCC. [ABSTRACT FROM AUTHOR]

Alternative splicing is a co-transcriptional process that significantly contributes to the molecular landscape of the cell. It plays a multifaceted role in shaping gene transcription, protein diversity, and functional adaptability in response to environmental cues. Recent studies demonstrate that drugs of abuse have a profound impact on alternative splicing patterns within different brain regions. Drugs like alcohol and cocaine modify the expression of genes responsible for encoding splicing factors, thereby influencing alternative splicing of crucial genes involved in neurotransmission, neurogenesis, and neuroinflammation. Notable examples of these alterations include alcohol-induced changes in splicing factors such as HSPA6 and PCBP1, as well as cocaine's impact on PTBP1 and SRSF11. Beyond the immediate effects of drug exposure, recent research has shed light on the role of alternative splicing in contributing to the risk of substance use disorders (SUDs). This is exemplified by exon skipping events in key genes like ELOVL7, which can elevate the risk of alcohol use disorder. Lastly, drugs of abuse can induce splicing alterations through epigenetic modifications. For example, cocaine exposure leads to alterations in levels of trimethylated lysine 36 of histone H3, which exhibits a robust association with alternative splicing and serves as a reliable predictor for exon exclusion. In summary, alternative splicing has emerged as a critical player in the complex interplay between drugs of abuse and the brain, offering insights into the molecular underpinnings of SUDs. [ABSTRACT FROM AUTHOR]

Accurate pre‐mRNA splicing is essential for proper protein translation; however, aberrant splicing is commonly observed in the context of cancer and genetic disorders. Notably, in genetic diseases, these splicing abnormalities often play a pivotal role. Substantial challenges persist in accurately identifying and classifying disease‐induced aberrant splicing, as well as in development of targeted therapeutic strategies. In this review, we examine prevalent forms of aberrant splicing and explore potential therapeutic approaches aimed at addressing these splicing‐related diseases. This summary contributes to a deeper understanding of the complexities about aberrant splicing and provide a foundation for the development of effective therapeutic interventions in the field of genetic disorders and cancer. [ABSTRACT FROM AUTHOR]

Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases. [ABSTRACT FROM AUTHOR]

Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal.

Abstract As aberrant alternative splicing by either dysregulation or mutations of splicing factors contributes to cancer initiation and progression, splicing factors are emerging as potential therapeutic targets for cancer therapy. Therefore, pharmacological modulators targeting splicing factors have been under development. Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific splicing factor, whose downregulation is associated with epithelial–mesenchymal transition (EMT) by regulating alternative splicing of multiple genes, such as CD44, CTNND1, ENAH, and FGFR2. Consistent with the downregulation of ESRP1 during EMT, it has been initially revealed that high ESRP1 expression is associated with favorable prognosis and ESRP1 plays a tumor-suppressive role in cancer progression. However, ESRP1 has been found to promote cancer progression in some cancers, such as breast and ovarian cancers, indicating that it plays a dual role in cancer progression depending on the type of cancer. Furthermore, recent studies have reported that ESRP1 affects tumor growth by regulating the metabolism of tumor cells or immune cell infiltration in the tumor microenvironment, suggesting the novel roles of ESRP1 in addition to EMT. ESRP1 expression was also associated with response to anticancer drugs. This review describes current understanding of the roles and mechanisms of ESRP1 in cancer progression, and further discusses the emerging novel roles of ESRP1 in cancer and recent attempts to target splicing factors for cancer therapy.

Abstract Alternative pre-mRNA splicing is a critical mechanism that generates multiple mRNA from a single gene, thereby increasing the diversity of the proteome. Recent research has highlighted the significance of specific splicing isoforms in cellular processes, particularly in regulating cell numbers. In this review, we examine the current understanding of the role of alternative splicing in controlling cancer cell growth and discuss specific splicing factors and isoforms and their molecular mechanisms in cancer progression. These isoforms have been found to intricately control signaling pathways crucial for cell cycle progression, proliferation, and apoptosis. Furthermore, studies have elucidated the characteristics and functional importance of splicing factors that influence cell numbers. Abnormal expression of oncogenic splicing isoforms and splicing factors, as well as disruptions in splicing caused by genetic mutations, have been implicated in the development and progression of tumors. Collectively, these findings provide valuable insights into the complex interplay between alternative splicing and cell proliferation, thereby suggesting the potential of alternative splicing as a therapeutic target for cancer.

Introduction: Peanut (Arachis hypogaea L.), also called groundnut is an important oil and cash crop grown widely in the world. The annual global production of groundnuts has increased to approximately 50 million tons, which provides a rich source of vegetable oils and proteins for humans. Low temperature (non-freezing) is one of the major factors restricting peanut growth, yield, and geographic distribution. Since the complexity of cold-resistance trait, the molecular mechanism of cold tolerance and related gene networks were largely unknown in peanut. Methods: In this study, comparative transcriptomic analysis of two peanut cultivars (SLH vs. ZH12) with differential cold tolerance under low temperature (10°C) was performed using Oxford Nanopore Technology (ONT) platform. Results and discussion: As a result, we identified 8,949 novel gene loci and 95,291 new/novel isoforms compared with the reference database. More differentially expressed genes (DEGs) were discovered in cold-sensitive cultivar (ZH12) than cold-tolerant cultivar (SLH), while more alternative splicing events were found in SLH compared to ZH12. Gene Ontology (GO) analyses of the common DEGs showed that the “response to stress”, “chloroplast part”, and “transcription factor activity” were the most enriched GO terms, indicating that photosynthesis process and transcription factors play crucial roles in cold stress response in peanut. We also detected a total of 708 differential alternative splicing genes (DASGs) under cold stress compared to normal condition. Intron retention (IR) and exon skipping (ES) were the most prevalent alternative splicing (AS) events. In total, 4,993 transcription factors and 292 splicing factors were detected, many of them had differential expression levels and/or underwent AS events in response to cold stress. Overexpression of two candidate genes (encoding trehalose-6-phosphatephosphatases, AhTPPs) in yeast improves cold tolerance. This study not only provides valuable resources for the study of cold resistance in peanut but also lay a foundation for genetic modification of cold regulators to enhance stress tolerance in crops [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 PRPF31. The expression level of PRPF31 is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within PRPF31 exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a PRPF31 1205C>A nonsense mutation were investigated; PRPF31 transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in PRPF31 mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold PRPF31 mRNA upregulation in the RP11 patient fibroblasts. The level of PRPF31 upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased PRPF31 expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations. [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) plays an important role in the co-transcription and post-transcriptional regulation of gene expression during mammalian spermatogenesis. The dzo is the male F1 offspring of an interspecific hybrid between a domestic bull (Bos taurus ♂) and a yak (Bos grunniens ♀) which exhibits male sterility. This study aimed to identify the testis-specific genes and AS associated with hybrid male sterility in dzo. The iDEP90 program and rMATS software were used to identify the differentially expressed genes (DEG) and differential alternative splicing genes (DSG) based on RNA-seq data from the liver (n = 9) and testis (n = 6) tissues of domestic cattle, yak, and dzo. Splicing factors (SF) were obtained from the AmiGO2 and the NCBI databases, and Pearson correlation analysis was performed on the differentially expressed SFs and DSGs. We focused on the testis-specific DEGs and DSGs between dzo and cattle and yak. Among the top 3,000 genes with the most significant variations between these 15 samples, a large number of genes showed testis-specific expression involved with spermatogenesis. Cluster analysis showed that the expression levels of these testis-specific genes were dysregulated during mitosis with a burst downregulation during the pachynema spermatocyte stage. The occurrence of AS events in the testis was about 2.5 fold greater than in the liver, with exon skipping being the major AS event (81.89% to 82.73%). A total of 74 DSGs were specifically expressed in the testis and were significantly enriched during meiosis I, synapsis, and in the piRNA biosynthesis pathways. Notably, STAG3 and DDX4 were of the exon skipping type, and DMC1 was a mutually exclusive exon. A total of 36 SFs were significantly different in dzo testis, compared with cattle and yak. DDX4 , SUGP1 , and EFTUD2 were potential SFs leading to abnormal AS of testis-specific genes in dzo. These results show that AS of testis-specific genes can affect synapsis and the piRNA biosynthetic processes in dzo, which may be important factors associated with hybrid male sterility in dzo. [ABSTRACT FROM AUTHOR]

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Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CUGBP ELAV-like family member 4 (CELF4), one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. An RNA sequencing (RNA-seq) dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNET cell lines were employed to assess CELF4 function in vitro and in vivo. PanNETs display markedly upregulated CELF4 expression, which is closely associated with malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating the mTOR pathway, suggesting its potential as therapeutic target.

As the most common nonepithelial malignancy, prostate adenocarcinoma (PRAD) is the fifth chief cause of cancer mortality in men. Distant metastasis often occurs in advanced PRAD and most patients are dying from it. However, the mechanism of PRAD progression and metastasis is still unclear. It's widely reported that more than 94% of genes are selectively splicing in humans and many isoforms are particularly related with cancer progression and metastasis. Spliceosome mutations occur in a mutually exclusive manner in breast cancer, and different components of spliceosomes are targets of somatic mutations in different types of breast cancer. Existing evidence strongly supports the key role of alternative splicing in breast cancer biology, and innovative tools are being developed to use splicing events for diagnostic and therapeutic purposes. In order to identify if the PRAD metastasis is associated with alternative splicing events (ASEs), the RNA sequencing data and ASEs data of 500 PRAD patients were retrieved from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. By Lasso regression, five genes were screened to construct the prediction model, with a good reliability by ROC curve. Additionally, results in both univariate and multivariate Cox regression analysis confirmed the well prognosis efficacy of the prediction model (both P < 0.001). Moreover, a potential splicing regulatory network was established and after multiple-database validation, we supposed that the signaling axis of HSPB1 up-regulating the PIP5K1C − 46,721 − AT (P < 0.001) might mediate the tumorigenesis, progression and metastasis of PRAD via the key members of Alzheimer's disease pathway (SRC, EGFR, MAPT, APP and PRKCA) (P < 0.001). [ABSTRACT FROM AUTHOR]

Alternative pre-mRNA splicing is a critical mechanism that generates multiple mRNA from a single gene, thereby increasing the diversity of the proteome. Recent research has highlighted the significance of specific splicing isoforms in cellular processes, particularly in regulating cell numbers. In this review, we examine the current understanding of the role of alternative splicing in controlling cancer cell growth and discuss specific splicing factors and isoforms and their molecular mechanisms in cancer progression. These isoforms have been found to intricately control signaling pathways crucial for cell cycle progression, proliferation, and apoptosis. Furthermore, studies have elucidated the characteristics and functional importance of splicing factors that influence cell numbers. Abnormal expression of oncogenic splicing isoforms and splicing factors, as well as disruptions in splicing caused by genetic mutations, have been implicated in the development and progression of tumors. Collectively, these findings provide valuable insights into the complex interplay between alternative splicing and cell proliferation, thereby suggesting the potential of alternative splicing as a therapeutic target for cancer. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most important risk factor for hepatocellular carcinoma (HCC). Alternative splicing (AS) plays an important role in NAFLD, HCC, and the transformation of NAFLD to HCC. AS in NAFLD and HCC is regulated by splicing factors and multiple epigenetic modifications. Drugs targeting AS are effective in treating NAFLD and HCC. AS targeting AS shows great potential to prevent NAFLD from developing into HCC. Non-alcoholic fatty liver disease (NAFLD) is becoming the most important risk factor for hepatocellular carcinoma (HCC). Understanding the progression of benign diseases to HCC is crucial for early prevention and reversal of malignant transformation. Alternative splicing (AS) of RNA plays a role in the pathogenicity, initiation, and transformation of liver disease. We summarize the changes or mutations in the activity of splicing factors in NAFLD and HCC, as well as the impact of AS mediated by epigenetic modifications such as DNA methylation, RNA methylation, histone modification, and protein phosphorylation on liver cell fate. We also summarize therapeutic methods and drugs that are helpful for treating NAFLD, HCC, and the early stages of NAFLD progression to HCC. [ABSTRACT FROM AUTHOR]

Abstract Background Alternative splicing (AS) of RNA is a fundamental biological process that shapes protein diversity. Many non-characteristic AS events are involved in the onset and development of acute myeloid leukemia (AML). Abnormal alterations in splicing factors (SFs), which regulate the onset of AS events, affect the process of splicing regulation. Hence, it is important to explore the relationship between SFs and the clinical features and biological processes of patients with AML. Methods This study focused on SFs of the classical heterogeneous nuclear ribonucleoprotein (hnRNP) family and arginine and serine/arginine-rich (SR) splicing factor family. We explored the relationship between the regulation patterns associated with the expression of SFs and clinicopathological factors and biological behaviors of AML based on a multi-omics approach. The biological functions of SRSF10 in AML were further analyzed using clinical samples and in vitro experiments. Results Most SFs were upregulated in AML samples and were associated with poor prognosis. The four splicing regulation patterns were characterized by differences in immune function, tumor mutation, signaling pathway activity, prognosis, and predicted response to chemotherapy and immunotherapy. A risk score model was constructed and validated as an independent prognostic factor for AML. Overall survival was significantly shorter in the high-risk score group. In addition, we confirmed that SRSF10 expression was significantly up-regulated in clinical samples of AML, and knockdown of SRSF10 inhibited the proliferation of AML cells and promoted apoptosis and G1 phase arrest during the cell cycle. Conclusion The analysis of splicing regulation patterns can help us better understand the differences in the tumor microenvironment of patients with AML and guide clinical decision-making and prognosis prediction. SRSF10 can be a potential therapeutic target and biomarker for AML.

Splicing factors (SFs) are proteins that control the alternative splicing (AS) of RNAs, which have been recognized as new cancer hallmarks. Their dysregulation has been found to be involved in many biological processes of cancer, such as carcinogenesis, proliferation, metastasis and senescence. Dysregulation of SFs has been demonstrated to contribute to the progression of prostate cancer (PCa). However, a comprehensive analysis of the prognosis value of SFs in PCa is limited. In this work, we systematically analysed 393 SFs to deeply characterize the expression patterns, clinical relevance and biological functions of SFs in PCa. We identified 53 survival‐related SFs that can stratify PCa into two de nove molecular subtypes with distinct mRNA expression and AS‐event expression patterns and displayed significant differences in pathway activity and clinical outcomes. An SF‐based classifier was established using LASSO‐COX regression with six key SFs (BCAS1, LSM3, DHX16, NOVA2, RBM47 and SNRPN), which showed promising prognosis‐prediction performance with a receiver operating characteristic (ROC) >0.700 in both the training and testing datasets, as well as in three external PCa cohorts (DKFZ, GSE70769 and GSE21035). CRISPR/CAS9 screening data and cell‐level functional analysis suggested that LSM3 and DHX16 are essential factors for the proliferation and cell cycle progression in PCa cells. This study proposes that SFs and AS events are potential multidimensional biomarkers for the diagnosis, prognosis and treatment of PCa. [ABSTRACT FROM AUTHOR]

Traditionally, the group 1 intron of the T4 td gene is used to generate a foreign circular sequence. However, the T4 system has been shown to be fairly inefficient in expressing circular RNA (circRNA). Here, a new method is developed to express circular sequences with high circularization efficiency to strengthen the confidence for future circRNA functional studies. CircRNA expression plasmids, constructed with different lengths derived from the actin intron (15‐nt, 30‐nt, 60‐nt, 100‐nt, 180‐nt) and T4 intron, are introduced into human and mouse cell lines 293T and B16. Junction detection and sequencing are used to determine successful circularization of introns and their expression efficiencies. An actin intron with a medium length (60‐nt–100‐nt) shows significantly increased efficiency of circularization, whereas intron‐100‐nt shows the best efficiency in most conditions. RNA pull‐down assays are designed to precipitate the splicing factors that are bound to the introns and intron/exon junction. The precipitated proteins are analyzed by mass spectrometry (MS), aiming to identify the possible underlying mechanism behind the high circularization efficiency. This expression system has been validated using different circRNAs, and such method shows potential in contributing to the expanding field of circRNA studies. [ABSTRACT FROM AUTHOR]

Cancer is characterized by the dysregulation of alternative splicing (AS). However, the comprehensive regulatory mechanisms of AS in lung adenocarcinoma (LUAD) are poorly understood. Here, we displayed the AS landscape in LUAD based on the integrated analyses of LUAD's multi-omics data. We identified 13,995 AS events in 6309 genes as differentially expressed alternative splicing events (DEASEs) mainly covering protein-coding genes. These DEASEs were strongly linked to "cancer hallmarks", such as apoptosis, DNA repair, cell cycle, cell proliferation, angiogenesis, immune response, generation of precursor metabolites and energy, p53 signaling pathway and PI3K-AKT signaling pathway. We further built a regulatory network connecting splicing factors (SFs) and DEASEs. In addition, RNA-binding protein (RBP) mutations that can affect DEASEs were investigated to find some potential cancer drivers. Further association analysis demonstrated that DNA methylation levels were highly correlated with DEASEs. In summary, our results can bring new insight into understanding the mechanism of AS and provide novel biomarkers for personalized medicine of LUAD. [ABSTRACT FROM AUTHOR]

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine‐rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6A methyltransferase, METTL3, by silencing. MeRIP‐qPCR, RNA pull‐down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6A‐modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co‐IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity‐based virtual screening in FDA‐approved drugs repurposed nebivolol, a β1‐adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. There are a number of current treatment options for CLL, including monoclonal antibodies, targeted drugs, chemotherapy, and different combinations of these. However, for those patients who are intrinsically treatment resistant, or relapse following initial responses, novel targeted therapies are still needed. Targeting the mouse double-minute-2 human homolog (MDM2), a primary negative regulator of p53, is an appealing therapeutic strategy for non-genotoxic reactivation of p53, since the TP53 gene is in its wild-type state at diagnosis in approximately 90% of patients. Mutated SF3B1 and TP53 are both associated with more aggressive disease, resistance to therapies and poorer overall survival for CLL. In this study, we performed a screen for SF3B1 and TP53 mutations and tested RG7388 (idasanutlin), a second-generation MDM2 inhibitor, in a cohort of CLL primary patient samples. SF3B1 mutations were detected in 24 of 195 cases (12.3%) and found associated with poor overall survival (hazard ratio [HR] 2.12, p = 0.032) and high CD38 expression (median CD38 (%) 32 vs. 5; p = 0.0087). The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors. [ABSTRACT FROM AUTHOR]

Steroid hormone signaling pathways are critical for organismal development and act through binding to nuclear receptors (NRs) driving transcriptional regulation. In this review, we summarize evidence for another—underrated—mechanism of action for steroid hormones: their ability to modulate the alternative splicing of pre–messenger RNA. Thirty years ago, pioneering studies used in vitro transfection of plasmids expressing alternative exons under the control of hormone-responsive promoters in cell lines. These studies demonstrated that steroid hormones binding to their NRs affected both gene transcription and alternative splicing outcomes. The advent of exon arrays and next-generation sequencing has allowed researchers to observe the effect of steroid hormones at the whole-transcriptome level. These studies demonstrate that steroid hormones regulate alternative splicing in a time-, gene-, and tissue-specific manner. We provide examples of the mechanisms by which steroid hormones regulate alternative splicing including 1) recruitment of dual-function proteins that behave as coregulators and splicing factors, 2) transcriptional regulation of splicing factor levels, 3) the alternative splicing of splicing factors or transcription factors that feed-forward regulate steroid hormone signaling, and 4) regulation of elongation rate. Experiments performed in vivo and in cancer cell lines highlight that steroid hormone–mediated alternative splicing occurs both in physiological and pathophysiologic states. Studying the effect of steroid hormones on alternative splicing is a fruitful avenue for research that should be exploited to discover new targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Serine-arginine (SR) proteins are essential splicing factors that promote numerous steps associated with mRNA processing and whose biological function is tightly regulated through multi-site phosphorylation. In the nucleus, the cdc2-like kinases (CLKs) phosphorylate SR proteins on their intrinsically disordered Arg-Ser (RS) domains, mobilizing them from storage speckles to the splicing machinery. The CLKs have disordered N termini that bind tightly to RS domains, enhancing SR protein phosphorylation. The N termini also promote nuclear localization of CLKs, but their transport mechanism is presently unknown. To explore cytoplasmic-nuclear transitions, several classical nuclear localization sequences in the N terminus of the CLK1 isoform were identified, but their mutation had no effect on subcellular localization. Rather, we found that CLK1 amplifies its presence in the nucleus by forming a stable complex with the SR protein substrate and appropriating its NLS for transport. These findings indicate that, along with their well-established roles in mRNA splicing, SR proteins use disordered protein-protein interactions to carry their kinase regulator from the cytoplasm to the nucleus.

RNA splicing refers to a process by which introns of a pre-mRNA are excised and the exons at both ends are joined together. Chloroplast introns are inherently self-splicing ribozymes, but over time, they have lost self-splicing ability due to the degeneration of intronic elements. Thus, the splicing of chloroplast introns relies heavily on nuclear-encoded splicing factors, which belong to diverse protein families. Different splicing factors and their shared intron targets are supposed to form ribonucleoprotein particles (RNPs) to facilitate intron splicing. As characterized in a previous review, around 14 chloroplast intron splicing factors were identified until 2010. However, only a few genetic and biochemical evidence has shown that these splicing factors are required for the splicing of one or several introns. The roles of splicing factors are generally believed to facilitate intron folding; however, the precise role of each protein in RNA splicing remains ambiguous. This may be because the precise binding site of most of these splicing factors remains unexplored. In the last decade, several new splicing factors have been identified. Also, several splicing factors were found to bind to specific sequences within introns, which enhanced the understanding of splicing factors. Here, we summarize recent progress on the splicing factors in land plant chloroplasts and discuss their possible roles in chloroplast RNA splicing based on previous studies.

Alternative splicing (AS) is a common and pivotal process for eukaryotic gene expression regulation, which enables a precursor RNA to produce multiple transcript variants with diverse cellular functions. Aberrant AS represents a hallmark of cancer, engaged in all stages of tumorigenesis from initiation to metastasis. Accumulating pieces of evidence have revealed the involvement of non-coding RNAs (ncRNAs) in regulating AS in human cancers. In this review, we overview the underlying mechanisms of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) modulated AS at diverse levels in human cancers, and summarize their regulatory functions in tumorigenesis.

Abstract Background Alternative splicing (AS) is an important channel for gene expression regulation and protein diversification, in addition to a major reason for the considerable differences in the number of genes and proteins in eukaryotes. In plants, U2 small nuclear ribonucleoprotein B″ (U2B″), a component of splicing complex U2 snRNP, plays an important role in AS. Currently, few studies have investigated plant U2B″, and its mechanism remains unclear. Result Phylogenetic analysis, including gene and protein structures, revealed that U2B″ is highly conserved in plants and typically contains two RNA recognition motifs. Subcellular localisation showed that OsU2B″ is located in the nucleus and cytoplasm, indicating that it has broad functions throughout the cell. Elemental analysis of the promoter region showed that it responded to numerous external stimuli, including hormones, stress, and light. Subsequent qPCR experiments examining response to stress (cold, salt, drought, and heavy metal cadmium) corroborated the findings. The prediction results of protein–protein interactions showed that its function is largely through a single pathway, mainly through interaction with snRNP proteins. Conclusion U2B″ is highly conserved in the plant kingdom, functions in the nucleus and cytoplasm, and participates in a wide range of processes in plant growth and development.