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Pre-mRNA processing factor 4 kinases (PRP4Ks) are crucial for eukaryotic organisms. These proteins are dual specificity kinases that phosphorylate the proteins involved in spliceosomal assembly during pre-mRNA processing. A repertoire of six TaPRP4K genes with conserved architecture is found in the allohexaploid genome of Triticum aestivum . These genes are evenly distributed on chromosomes 4 and 5. The phylogenetic analysis reveals the PRP4Ks’ distinct groups of various monocots and dicots. The DMFA, EGY/DH-box and a few other motifs of the protein kinase domain are found conserved in all the TaPRP4K proteins. Additionally, an atypical protein kinase domain, ABC1 is also present, which increases the structural complexity of each TaPRP4Ks. The promoter sequence analysis reveals the occurrence of light, growth, hormone and stress-related cis-regulatory elements, which shows interaction with a diverse group of transcription factors (TFs). TaPRP4K genes are also presumed to be regulated by miRNAs associated with plant growth and stress response. In addition, TaPRP4Ks display interaction with numerous other proteins such as CLO, BRR2a, SMU1, STA1, etc., which are involved in the regulation of the splicing mechanism. The expression study reveals significant expression of certain TaPRP4K genes in above-ground tissues, which indicates their roles in vegetative and reproductive tissue development. Further, TaPRP4K2 group genes show upregulated expression during salt stress and fungus ( Blumeria graminis f. sp. tritici ) infestation, which suggests their role in both abiotic and biotic stress response. Our study provides numerous important features and probable functioning of TaPRP4K genes, which would be useful in the detailed functional characterization of these genes in future studies.

Treating fungal infections is challenging and frequently requires long-term courses of antifungal drugs. Considering the limited number of existing antifungal drugs, it is crucial to evaluate the possibility of repositioning drugs with antifungal properties and to revisit older antifungals for applications in combined therapy, which could widen the range of therapeutic possibilities. Undecanoic acid is a saturated medium-chain fatty acid with known antifungal effects; however, its antifungal properties have not been extensively explored. Recent advances indicate that the toxic effect of undecanoic acid involves modulation of fungal metabolism through its effects on the expression of fungal genes that are critical for virulence. Additionally, undecanoic acid is suitable for chemical modification and might be useful in synergic therapies. This review highlights the use of undecanoic acid in antifungal treatments, reinforcing its known activity against dermatophytes. Specifically, in Trichophyton rubrum , against which the activity of undecanoic acid has been most widely studied, undecanoic acid elicits profound effects on pivotal processes in the cell wall, membrane assembly, lipid metabolism, pathogenesis, and even mRNA processing. Considering the known antifungal activities and associated mechanisms of undecanoic acid, its potential use in combination therapy, and the ability to modify the parent compound structure, undecanoic acid shows promise as a novel therapeutic against fungal infections.

To ensure efficient and accurate gene expression, pre-mRNA processing and mRNA export need to be balanced. However, how this balance is ensured remains largely unclear. Here, we found that SF3b, a component of U2 snRNP that participates in splicing and 3′ processing of pre-mRNAs, interacts with the key mRNA export adaptor THO in vivo and in vitro. Depletion of SF3b reduces THO binding with the mRNA and causes nuclear mRNA retention. Consistently, introducing SF3b binding sites into the mRNA enhances THO recruitment and nuclear export in a dose-dependent manner. These data demonstrate a role of SF3b in promoting mRNA export. In support of this role, SF3b binds with mature mRNAs in the cells. Intriguingly, disruption of U2 snRNP by using a U2 antisense morpholino oligonucleotide does not inhibit, but promotes, the role of SF3b in mRNA export as a result of enhanced SF3b–THO interaction and THO recruitment to the mRNA. Together, our study uncovers a U2-snRNP–independent role of SF3b in mRNA export and suggests that SF3b contributes to balancing pre-mRNA processing and mRNA export.

mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.

The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre‐mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full‐length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full‐length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full‐length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro‐opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild‐type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood–brain barrier and its systemic delivery reduced food intake in wild‐type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre‐mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader–Willi syndrome. Synopsis The serotonin 2C receptor regulates food uptake and undergoes alternative pre‐mRNA splicing; the ratio of the two spliced isoforms (truncated versus full length) controls the activity of serotonergic neurons. An oligonucleotide promotes the formation of the full‐length receptor and reduces food intake. The ratio of serotonin 2C receptor splicing isoforms controls food intake. This ratio can be changed using a synthetic oligonucleotide. The oligonucleotide mimics a naturally trans‐acting RNA, SNORD115, that is not expressed in Prader–Willi syndrome, a genetic form of obesity. Through heterodimerization with other receptors, the isoform ratio could impact on various receptor systems contributing to Prader–Willi syndrome. Graphical Abstract The serotonin 2C receptor regulates food uptake and undergoes alternative pre‐mRNA splicing; the ratio of the two spliced isoforms (truncated versus full length) controls the activity of serotonergic neurons. An oligonucleotide promotes the formation of the full‐length receptor and reduces food intake.

Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to -regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.

The PI3K/Akt signaling pathway is a major driving force in a variety of cellular functions. Dysregulation of this pathway has been implicated in many human diseases including cancer. While the activity of the cytoplasmic PI3K/Akt pathway has been extensively studied, the functions of these molecules and their effector proteins within the nucleus are poorly understood. Harboring key cellular processes such as DNA replication and repair as well as nascent messenger RNA transcription, the nucleus provides a unique compartmental environment for protein-protein and protein-DNA/RNA interactions required for cell survival, growth, and proliferation. Here we summarize recent advances made toward elucidating the nuclear PI3K/Akt signaling cascade and its key components within the nucleus as they pertain to cell growth and tumorigenesis. This review covers the spatial and temporal localization of the major nuclear kinases having PI3K activities and the counteracting phosphatases as well as the role of nuclear PI3K/Akt signaling in mRNA processing and exportation, DNA replication and repair, ribosome biogenesis, cell survival, and tumorigenesis.

Tumor immune microenvironment is strongly associated with the malignancy behavior of hepatocellular carcinoma (HCC). However, the immune function and regulatory mechanisms of B cells in HCC remain unclear. The expression differences between B cell high‐ and low‐infiltration HCC samples are explored to identify the key regulator. Pre‐mRNA processing factor 19 (PRP19) expression is increased in B cell low‐infiltrated tissues and negatively correlated with the B cell marker, CD20. Inhibition of PRP19 expression promoted B cell infiltration in tumor tissue and impeded HCC growth. Mechanically, the co‐immunoprecipitation (Co‐IP) assay revealed that PRP19 interacts with DEAD‐box helicase 5 (DDX5), leading to ubiquitination and degradation of the DDX5 protein. The attenuated DDX5 impairs CXCL12 mRNA stability to suppress B cell recruitment and plasma cell differentiation via CXCL12/CXCR4 axis. Moreover, the adoptive transfer of CXCR4+ B cells combined with CXCL12 treatment in mice models effectively inhibits HCC development by reshaping the immune response. The expression of PRP19, DDX5, and infiltrating B cells are recognized as clinical prognosis indicators for HCC patients. Overall, this study provides valuable insights into the clinical benefits of HCC immunotherapy by targeting PRP19 and modulating tumor‐infiltrating B cell immune function. This study investigates the role of B cells in the tumor immune microenvironment of HCC. It identifies PRP19 as a key regulator, with its high expression linked to low B cell infiltration. Inhibiting PRP19 enhances B cell migration and differentiation to reduce HCC growth. The findings suggest that targeting PRP19 may improve HCC immunotherapy.

Aging in females affects the ovaries before any other organ. This has a significant impact on women’s health. Aging results in the gradual depletion of ovarian follicles and a decline in oocyte quality. Studies have shown that cellular changes within ovaries manifest before the depletion of ovarian follicles. To understand the molecular mechanisms underlying these changes, we conducted a comprehensive analysis of gene expression changes in aging mouse ovaries. When RNA sequencing data from 6-month-old mice were compared to those from 12-month-old mice, we identified numerous differentially expressed genes, as well as transcript variants. Transcript variants arise from alternative transcription start sites (TSSs) and alternative pre-mRNA processing. Therefore, we further analyzed a specific set of regulators for these cellular processes. Our findings indicate that ovarian aging alters the expression of epigenetic regulators (ERs) and transcription factors (TFs) that are involved in alternative TSS usage. Ovarian aging also affects the expression of RNA-binding proteins (RBPs) and spliceosome components (SPs), which are essential for pre-mRNA processing. We noticed that variations in transcript variants were more pronounced than those found through gene expression analysis. While 8% of the known TFs and ERs were differentially expressed at the gene level, this increased to 30% at the transcript variant level. Similarly, 3% of the known RBPs but no known SPs were differentially expressed at the gene level, while this increased to 30% at the transcript variant level. These observations highlight the importance of focusing on transcript variants and their functions in aging research, as they may provide insight into the underlying biological processes involved.

Recent advances reveal mRNA 3′end processing as a highly regulated process that fine‐tunes posttranscriptional gene expression. This process can affect the site and/or the efficiency of 3′end processing, controlling the quality and the quantity of substrate mRNAs. The regulation of 3′end processing plays a central role in fundamental physiology such as blood coagulation and innate immunity. In addition, errors in mRNA 3′end processing have been associated with a broad spectrum of human diseases, including cancer. We summarize and discuss the paradigmatic shift in the understanding of 3′end processing as a mechanism of posttranscriptional gene regulation that has reached clinical medicine. Graphical Abstract By connecting human diseases with mRNA 3' end formation and process, this comprehensive review provides a timely and useful memento to biologists and clinicians that the deregulation of gene expression can terribly affect human health.