Abstract:Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we d… Show more
“…In addition, we found other domains frequently associated to RBPs, such as the SAP domain ( Aravind and Koonin, 2000 ), the DDX ( Gilman et al, 2017 ) and the KH ( Valverde et al, 2008 ) domains, also known to be R-methylated ( Figure 2C ). The fact that the 14-3-3 protein family was also enriched in the interface fraction is particularly intriguing, because these proteins were the first identified containing a reader motif for phospho-serine/threonine ( Espejo et al, 2017 ); hence this result supports the idea of a possible cross-talk between R-methylation and Ser/Thr-phosphorylation ( Chen et al, 2016 ; Liu et al, 2020 ; Smith et al, 2020 ).…”
RNA binding proteins (RBPs) bind RNAs through specific RNA-binding domains, generating multi-molecular complexes known as ribonucleoproteins (RNPs). Various post-translational modifications (PTMs) have been described to regulate RBP structure, subcellular localization, and interactions with other proteins or RNAs. Recent proteome-wide experiments showed that RBPs are the most representative group within the class of arginine (R)-methylated proteins. Moreover, emerging evidence suggests that this modification plays a role in the regulation of RBP-RNA interactions. Nevertheless, a systematic analysis of how changes in protein-R-methylation can affect globally RBPs-RNA interactions is still missing. We describe here a quantitative proteomics approach to profile global changes of RBP-RNA interactions upon the modulation of type I and II protein arginine methyltransferases (PRMTs). By coupling the recently described Orthogonal Organic Phase Separation (OOPS) strategy with the Stable Isotope Labelling with Amino acids in Cell culture (SILAC) and pharmacological modulation of PRMTs, we profiled RNA-protein interaction dynamics in dependence of protein-R-methylation. Data are available via ProteomeXchange with identifier PXD024601.
“…In addition, we found other domains frequently associated to RBPs, such as the SAP domain ( Aravind and Koonin, 2000 ), the DDX ( Gilman et al, 2017 ) and the KH ( Valverde et al, 2008 ) domains, also known to be R-methylated ( Figure 2C ). The fact that the 14-3-3 protein family was also enriched in the interface fraction is particularly intriguing, because these proteins were the first identified containing a reader motif for phospho-serine/threonine ( Espejo et al, 2017 ); hence this result supports the idea of a possible cross-talk between R-methylation and Ser/Thr-phosphorylation ( Chen et al, 2016 ; Liu et al, 2020 ; Smith et al, 2020 ).…”
RNA binding proteins (RBPs) bind RNAs through specific RNA-binding domains, generating multi-molecular complexes known as ribonucleoproteins (RNPs). Various post-translational modifications (PTMs) have been described to regulate RBP structure, subcellular localization, and interactions with other proteins or RNAs. Recent proteome-wide experiments showed that RBPs are the most representative group within the class of arginine (R)-methylated proteins. Moreover, emerging evidence suggests that this modification plays a role in the regulation of RBP-RNA interactions. Nevertheless, a systematic analysis of how changes in protein-R-methylation can affect globally RBPs-RNA interactions is still missing. We describe here a quantitative proteomics approach to profile global changes of RBP-RNA interactions upon the modulation of type I and II protein arginine methyltransferases (PRMTs). By coupling the recently described Orthogonal Organic Phase Separation (OOPS) strategy with the Stable Isotope Labelling with Amino acids in Cell culture (SILAC) and pharmacological modulation of PRMTs, we profiled RNA-protein interaction dynamics in dependence of protein-R-methylation. Data are available via ProteomeXchange with identifier PXD024601.
“…To our knowledge, this is the first study to report the association of hypomethylation of the HIST2H2BF promoter with transcriptional upregulation of HIST2H2BF in CRC. CSCs account for tumor initiation, development, progression, and metastasis (29,30). CSCs are also attributed to tumor relapse, resistance to chemotherapy, and radiation therapy, which are common clinical events (31).…”
Section: Discussionmentioning
confidence: 99%
“…CSCs account for tumor initiation, development, progression, and metastasis ( 29 , 30 ). CSCs are also attributed to tumor relapse, resistance to chemotherapy, and radiation therapy, which are common clinical events ( 31 ).…”
BackgroundGrowing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC.MethodsHIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed.ResultsHIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties.ConclusionOur study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.
“…PRMT5 and -9 are type II PRMTs. PRMT7 was initially described as a Type II PRMT and subsequently characterised as type III (Zurita-Lopez et al 2012 ) but recent reports have again reported Type II activity (Jeong et al 2020 ; Vuong et al 2020 ; Liu et al 2020a ). Fig.…”
Section: Arginine Methylation and Protein Arginine Methyltransferasesmentioning
Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.
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