Abstract:Cells adapt to their environment by linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. Among these, mechanisms that couple environmental cues to the regulation of protein translation are not well understood. Chemical modifications of RNA allow rapid cellular responses to external stimuli by modulating a wide range of fundamental biochemical properties and processes, including the stability, splicing and translation of messenger RNA. In this Re… Show more
In this review we explore the regulation of mRNA cap formation and its impact on mammalian cells. The mRNA cap is a highly methylated modification of the 5′ end of RNA pol II-transcribed RNA. It protects RNA from degradation, recruits complexes involved in RNA processing, export and translation initiation, and marks cellular mRNA as “self” to avoid recognition by the innate immune system. The mRNA cap can be viewed as a unique mark which selects RNA pol II transcripts for specific processing and translation. Over recent years, examples of regulation of mRNA cap formation have emerged, induced by oncogenes, developmental pathways and during the cell cycle. These signalling pathways regulate the rate and extent of mRNA cap formation, resulting in changes in gene expression, cell physiology and cell function.
In this review we explore the regulation of mRNA cap formation and its impact on mammalian cells. The mRNA cap is a highly methylated modification of the 5′ end of RNA pol II-transcribed RNA. It protects RNA from degradation, recruits complexes involved in RNA processing, export and translation initiation, and marks cellular mRNA as “self” to avoid recognition by the innate immune system. The mRNA cap can be viewed as a unique mark which selects RNA pol II transcripts for specific processing and translation. Over recent years, examples of regulation of mRNA cap formation have emerged, induced by oncogenes, developmental pathways and during the cell cycle. These signalling pathways regulate the rate and extent of mRNA cap formation, resulting in changes in gene expression, cell physiology and cell function.
“…The role of chemical modifications of RNA has been extensively explored and discussed (1, 15, 16). However, with the exception of some post-transcriptional chemical marks on certain subtypes of ncRNAs, such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), that have been known for decades, the focus of research in this area has mainly been on the impact of these modifications on mRNA.…”
Section: Chemical Modifications Of Ncrnas and Their Functionsmentioning
confidence: 99%
“…On the other hand, queuosine substitution of guanosine at the wobble position of tRNAs and its presence could alter mRNA decoding (31). Overall, m 6 A is the most prevalent internal modification found in mRNA (15), and with more than an estimated 20,000 unique sites in lncRNAs (32), whereas m 5 C is most prevalent in tRNAs and RNAs, with more than 30,000 unique sites in lncRNAs (32). Around 2,000 unique sites have been proposed for pseudouridine in lncRNAs (32), but, for this and for other RNA modifications, emerging epitranscriptomic data and further posterior validation experiments could provide different numbers.…”
Section: Chemical Modifications Of Ncrnas and Their Functionsmentioning
The activity of RNA is controlled by different types of post-transcriptional modifications, such as the addition of methyl groups and other chemical and structural changes, that have been recently described in human cells by high-throughput sequencing. Herein, we will discuss how the so called epitranscriptome is disrupted in cancer and what the contribution of its writers, readers and erasers to the process of cellular transformation is, particularly focusing in the epigenetic modifications of ncRNAs.
“…Covalent modifications are also commonly found in RNA, but their precise role in regulating gene expression and translation remains less well understood. However, RNA modifications are crucial for development and aberrant deposition of RNA modifications can lead to complex human diseases, including neurodevelopmental disorders and cancer (Frye and Blanco, 2016, Popis et al., 2016). …”
SummaryLoss-of-function mutations in the cytosine-5 RNA methylase NSUN2 cause neurodevelopmental disorders in humans, yet the underlying cellular processes leading to the symptoms that include microcephaly remain unclear. Here, we show that NSUN2 is expressed in early neuroepithelial progenitors of the developing human brain, and its expression is gradually reduced during differentiation of human neuroepithelial stem (NES) cells in vitro. In the developing Nsun2−/− mouse cerebral cortex, intermediate progenitors accumulate and upper-layer neurons decrease. Loss of NSUN2-mediated methylation of tRNA increases their endonucleolytic cleavage by angiogenin, and 5′ tRNA fragments accumulate in Nsun2−/− brains. Neural differentiation of NES cells is impaired by both NSUN2 depletion and the presence of angiogenin. Since repression of NSUN2 also inhibited neural cell migration toward the chemoattractant fibroblast growth factor 2, we conclude that the impaired differentiation capacity in the absence of NSUN2 may be driven by the inability to efficiently respond to growth factors.
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