Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes, including transcription, RNA processing, signal ...transduction cascades, the DNA damage response and liquid-liquid phase separation. Recent studies have provided considerable advances in the development of experimental tools and the identification of clinically relevant PRMT inhibitors. In this review, we discuss the regulation of PRMTs, their various cellular roles and the clinical relevance of PRMT inhibitors for the therapy of neurodegenerative diseases and cancer.
RNA‐binding proteins (RBPs) are essential players in RNA metabolism including key cellular processes from pre‐mRNA splicing to mRNA translation. The K homology‐type QUAKING RBP is emerging as a vital ...factor for oligodendrocytes, monocytes/macrophages, endothelial cell, and myocyte function. Interestingly, the qkI gene has now been identified as the culprit gene for a patient with intellectual disabilities and is translocated in a pediatric ganglioglioma as a fusion protein with MYB. In this review, we will focus on the emerging discoveries of the QKI proteins as well as highlight the recent advances in understanding the role of QKI in human disease pathology including myelin disorders, schizophrenia and cancer. WIREs RNA 2016, 7:399–412. doi: 10.1002/wrna.1344
This article is categorized under:
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease
Sam68 is a known sequence-specific RNA binding protein that regulates alternative splicing events during the cell cycle and apoptosis. Sam68 has also been shown to influence transcription, but the ...molecular mechanism remains undefined. Herein we identify Sam68 as a transcriptional coactivator of the p53 tumor suppressor in response to DNA damage. Using CRISPR/Cas9 generated isogenic HCT116 Sam68
cell lines wild type or deficient for p53, we show that Sam68 is required for the efficient transactivation of p53 target genes. Consistently, Sam68 depletion caused defects in DNA damage-induced cell cycle arrest and apoptosis mediated by p53. Mechanistically, we demonstrate that Sam68 physically interacted with p53 in an RNA-dependent manner, and that this interaction was essential for the coactivator function of Sam68. Furthermore, we show that both Sam68 and p53 were recruited to promoters of p53-responsive genes, suggesting interdependence. Finally, Sam68 acted in concert with the p53 long noncoding RNA (lncRNA) target PR-lncRNA-1 for p53 recruitment, implicating a positive-feedback mechanism in which lncRNAs induced by the Sam68/p53 complex can enhance p53 transcriptional activity. These findings define a hitherto novel mechanism of action for Sam68 in governing p53 transcriptional activation, and represent the first report of Sam68 in the regulation of tumor suppressor activities.
•A systematic review and meta-analysis assessed the efficacy of intravenous ketamine infusions in patients presenting TRD•Improvement in clinical depression measures were observed within 24 hours ...following a single ketamine infusion•Ketamine's obtained benefits were enhanced and prolonged following multiple infusions•Results provide support for ketamine as an innovative and promising treatment in the rapid management of depressive symptoms in TRD
Sub-anaesthetic administration of ketamine is an emerging practice in patients presenting treatment resistant depression (TRD), however several outstanding questions have yet to be answered.
To evaluate the effect of intravenous ketamine infusion for patients presenting TRD on depression scores, clinical remission and response rates, and to assess its efficacy over both time and frequency.
Five databases were searched up to January 4th 2019 to include primary studies evaluating the use of sub-anaesthetic dose of ketamine in adults presenting TRD. Two reviewers independently performed the study selection, quality assessment and data extraction. Results were summarised in a narrative synthesis. A meta-analysis using a random effects model was performed when possible to examine changes in standardized mean differences and odds ratios of outcome measures at 4 hours, 24 hours, or 7 days post-infusion.
Twenty-eight studies in 35 publications were included. A strong ketamine effect was observed within 4 hours following a single infusion, and peaked at 24 hours. Ketamine's effectiveness was still present, yet somewhat diminished, 7 days post-infusion. Multiple infusions resulted in an enhanced and prolonged ketamine effect.
Due to insufficient data, long-term safety and efficacy of ketamine utilisation in patients presenting TRD are yet to be investigated.
Results provide support for the use of ketamine in the rapid management of depressive symptoms. While ketamine appears promising in the short-term treatment of TRD, more clinical and experimental data is needed with regards to the efficacy, tolerance and security of long-term administration of ketamine.
Post-translational modifications are well-known modulators of DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition ...of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine methylated proteins implicated in a variety of cellular processes including RNA metabolism, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMTs in DNA damage signaling and its importance for maintaining genomic stability.
Random Positioning Machines (RPMs) have been used since many years as a ground-based model to simulate microgravity. In this review we discuss several aspects of the RPM. Recent technological ...development has expanded the operative range of the RPM substantially. New possibilities of live cell imaging and partial gravity simulations, for example, are of particular interest. For obtaining valuable and reliable results from RPM experiments, the appropriate use of the RPM is of utmost importance. The simulation of microgravity requires that the RPM’s rotation is faster than the biological process under study, but not so fast that undesired side effects appear. It remains a legitimate question, however, whether the RPM can accurately and reliably simulate microgravity conditions comparable to real microgravity in space. We attempt to answer this question by mathematically analyzing the forces working on the samples while they are mounted on the operating RPM and by comparing data obtained under real microgravity in space and simulated microgravity on the RPM. In conclusion and after taking the mentioned constraints into consideration, we are convinced that simulated microgravity experiments on the RPM are a valid alternative for conducting examinations on the influence of the force of gravity in a fast and straightforward approach.
Many species use chemicals to communicate. In humans, there is increasing evidence that chemicals conveyed by the body are extremely important in interpersonal relationships. However, many aspects of ...chemical communication remain to be explored to fully understand this function in humans. The aim of this article is to identify relevant challenges in this field, with a focus on human attractiveness in the context of reproduction, and to put forward roadmaps for future studies that will hopefully extend to a wider range of social interactions. The first challenge consists in not being limited to body (mal)odours from the axilla. Preliminary data on how the odour of the face and head is perceived are presented. Second, there is a crucial need to increase our knowledge of the chemical bases of human chemical communication. Third, cross-cultural approaches must not be overlooked, because they have a major input in understanding the universal and culture-specific aspects of chemical communication. Fourth, the influence of specific cultural practices such as contraceptive and fragrance use is likely to be prominent and, therefore, needs to be well described. The fifth and last challenge for research projects in this field is the integration of different disciplines such as behavioural sciences, social sciences, neurosciences and microbiology. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.
Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of ...cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb) tumor suppressor pathways. Restoring the KDM4A expression contributed to bypass of miR-137-induced senescence and inhibition of endogenous miR-137 with an miRNA sponge-compromised Ras-induced senescence. miR-137 levels are significantly reduced in human pancreatic tumors, consistent with previous studies revealing a defective senescence response in this cancer type. Restoration of miR-137 expression inhibited proliferation and promoted senescence of pancreatic cancer cells. These results suggest that modulating levels of miR-137 may be important for triggering tumor suppressor networks in pancreatic cancer.
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•miR-137 triggers the p53 and p16INK4A tumor suppressor pathways•KDM4A is a target of miR-137 during Ras-induced senescence•Loss of miR-137 contributes to the bypass of Ras-induced senescence•Restoration of miR-137 expression induces senescence in pancreatic cancer cells
Depletion of KDM4A in response to Ras is a key event mediating Ras-induced senescence in normal cells. Neault et al. show that Ras-induced miR-137 targets KDM4A and activates downstream p53 and p16INK4A tumor suppressor pathways to promote cell-cycle arrest and senescence.
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