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The multifaceted eukaryotic cap structure

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Abstract The 5′ cap structure is added onto RNA polymerase II transcripts soon after initiation of transcription and modulates several post‐transcriptional regulatory events involved in RNA maturation. It is also required for stimulating translation initiation of many cytoplasmic mRNAs and serves to protect mRNAs from degradation. These functional properties of the cap are mediated by several cap binding proteins (CBPs) involved in nuclear and cytoplasmic gene expression steps. The role that CBPs play in gene regulation, as well as the biophysical nature by which they recognize the cap, is quite intricate. Differences in mechanisms of capping as well as nuances in cap recognition speak to the potential of targeting these processes for drug development. In this review, we focus on recent findings concerning the cap epitranscriptome, our understanding of cap binding by different CBPs, and explore therapeutic targeting of CBP‐cap interaction. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Processing > Capping and 5′ End Modifications Translation > Translation Mechanisms
RNA cap and capping mechanisms. (a) The cap consists of 7‐methylguanosine linked to the first transcribed nucleoside of the mRNA through a 5′‐5′ triphosphate bridge. The N7 methyl residue is highlighted in magenta. The 2′‐O‐methyl groups of the first and second nucleosides are highlighted in turquoise and constitute Cap 1 and Cap 2 structures, respectively. (b) Canonical capping pathway. The canonical pathway involves the activity of an RNA triphosphatase (RTPase) required to hydrolyze the γ‐phosphate from the nascent mRNA. A guanylytransferase (GTase) then transfers a GMP molecule (via the formation of a GTase‐GMP covalent intermediate) onto the 5′ terminal β‐phosphate. In vertebrates, both the RTPase and GTase activities are present within RNGTT. This is followed by (guanine‐N7)‐methyltransferase (RNMT) transferring a methyl group from S‐adenosyl‐L‐methionine to the N7 position of the terminal guanine to form a Cap 0 structure. Subsequent (nucleoside‐2′‐O)‐methyltransferases form Cap 1 (CMTR1) and Cap 2 (CMTR2) structures. When the penultimate nucleoside is adenosine, CAPAM will transfer a methyl residue to the N6 position of adenine. N refers to the nitrogenous bases adenine, cytosine, guanine, and uracil
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Structure of cap analogs that have been designed with the aim of avoiding mispriming during transcription initiation and improving resistance to cellular decapping activities
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Cut away view of cap binding pockets of the indicated CBPs. The N7‐methyl position of the cap is denoted by a small grey nob. Note that in some of the images some of the phosphate groups are outside the depth of field shown (Mazza et al., 2002; Niedzwiecka et al., 2002; Rosettani et al., 2007; Lahr et al. 2017; Hodel et al., 1998; Pautus et al., 2013; Xie et al, 2016)
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Surface representation of cap binding pockets of the indicated CBPs. The N7‐methyl position of the cap is denoted by a small grey nob (Mazza et al., 2002; Niedzwiecka et al., 2002; Rosettani et al., 2007; Lahr et al. 2017; Hodel, Gershon, & Quiocho,1998; Pautus et al., 2013; Xie et al, 2016)
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Binding to the m7G moiety of the cap by various cap‐binding proteins. Diagrams were generated in PyMOL software using the following PDB accession numbers: CBP20 (1H2T; Mazza et al., 2001), eIF4E (1L8B; Niedzwiecka et al., 2002), 4EHP (2JGB; Rosettani, Knapp, Vismara, Rusconi & Cameron, 2007), LARP1 (5V4R; Lahr et al., 2017), VP39 (1AV6; Hodel, Gershon, & Quiocho, 1998), influenza A H5N1 PB2 (4CB4; Pautus et al., 2013), and influenza B Lee PB2 (5EFA; Xie et al., 2016)
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Cap composition, as defined by CapQuant, in mouse tissue and yeast. The relative abundance of different cap structures found in mouse liver and kidney, as well as Saccharomyces cerevisiae, are shown as pie charts. Mean values were taken from J. Wang et al. (2019)
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Translation > Translation Mechanisms
RNA Processing > Capping and 5′ End Modifications
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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