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Long noncoding RNA‐dependent methylation of nonhistone proteins

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Abstract In the last decade, an intriguing new paradigm of regulation has emerged in which some transcripts longer than 200 nucleotides and no coding potential, long noncoding RNA (lncRNAs), exhibit the capability to control posttranslational modifications of nonhistone proteins in both invertebrates and vertebrates. The extent of such a regulation is still largely unknown. We performed a systematic review to identify and evaluate the potential impact of lncRNA‐dependent methylation of nonhistone proteins. Collectively, these lncRNAs primarily act as scaffolds upon which methyltransferases (MTases) and targets are brought in proximity. In this manner, the N‐MTase activity of EZH2, protein arginine‐MTase 1/4/5, and SMYD2 is exploited to modulate the stability or the compartmentalization of several nonhistone proteins with roles in cell signaling, gene expression, and RNA processing. Moreover, these lncRNAs can indirectly affect the methylation of nonhistone proteins by transcriptional or posttranscriptional regulation of MTases. Strikingly, the lncRNAs/MTases/nonhistone proteins networking seem to be relevant to carcinogenesis and neurological disorders. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Preferred reporting items for systematic reviews and meta‐analyses (PRISMA) flow diagram of this systematic review
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Long noncoding RNAs (lncRNAs) regulate abundance of N‐methyltransferases to affect methylation of nonhistone proteins. Some lncRNAs regulate either the expression level or the stability of protein arginine‐methyltransferase (PRMTs) that is relevant for the methylation of non‐histone proteins. (a) Drosophila hsrω transcriptionally and posttranscriptionally regulates the abundance of PRMT5 and PRMT1, respectively, leading to methylation of FUS. Furthermore, the PRMT5‐dependent symmetrical arginine (R)‐dimethylation of FUS (SDMA‐FUS) leads to FUS proteasomal degradation, while the PRMT1‐dependent asymmetrical R‐dimethylation of FUS (ADMA‐FUS) involves the nucleo‐cytoplasmic FUS shuttling. Both FUS turnover and cellular localization have been found to be critical for neuronal toxicity and interestingly, to be regulated by hsrω/PRMTs axis. (b) The antisense lncRNA ST7‐AS1 binds to and protects PRMT4 from ubiquitin‐dependent degradation. Since PRMT4 can methylate Sox‐2, a pluripotent transcription factor, ST7‐AS1 has been proposed to play as an oncogene through the PRMT4‐Sox‐2 axis to enhance Sox‐2 self‐association and transactivation activity. (c) The lncRNA LINC01138 posttranscriptionally regulates PRMT5. By binding to PRMT5, LINC01138 can indeed prevent the PRMT5 proteasomal degradation. In addition, as shown in Figure 2, LINC01138 also plays a role as a scaffold to promote PRMT5‐SRBP1 interaction. Finally, the SRBP1 R‐methylation driven LINC01138/PRMT5 RNA–protein complex modulates the lipid desaturation in a fashion that is relevant for cell proliferation in clear cell renal cell carcinoma. Created by BioRender.com
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Long noncoding RNAs (lncRNAs) scaffold N‐methyltransferases (MTases) to drive methylation of non‐histone proteins. Cartoons depict the functions of lncRNAs in scaffolding N‐MTases and their targets. (a) The lncRNA TUG1 showed an evolutionarily conserved function to bind the N‐MTase EZH2 in rats, mice, and humans. Previous finding showed TUG1/EZH2 RNA–protein complex to involve H3K27 methylation in the nucleus (Katsushima et al., 2016) while R. Chen, Kong, et al. (2017) identified such a complex being also able to methylate actin in the cytoplasm. (b) Posttranslation modifications are key events to regulate the Hippo/Yap cell signaling pathway. Hippo switches from inactive to active depending on its phosphorylation (p‐Hippo) or methylation (Met‐Hippo) status. Active Hippo (p‐Hippo) leads to Yap phosphorylation (p‐Yap) and further binds to 14–3‐3 protein. In turn, inactive Hippo (Met‐Hippo) causes the Yap to translocate into the nucleus as a functional active transcription factor. (c) The Wnt signaling pathway functions by regulating the amount of the transcriptional co‐activator β‐catenin that controls key developmental gene expression programs. Therefore, β‐catenin is the central downstream effector of Wnt. Phosphorylation of β‐catenin leads to β‐catenin proteasomal degradation, while a lncRNA‐dependent either lysine (K)‐ or arginine (R)‐methylation by β‐Catm/EZH2 and LINC00052/SMYD2 RNA–protein complexes, respectively, activates the β‐catenin in the nucleus. (d) R‐methylation of SRBP1 by the LINC01138/PRMT5 RNA‐protein complex affects the lipids composition in a fashion that an increased desaturated lipids content combines with higher cancer invasiveness. Created by BioRender.com
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