Abstract
Simple SummaryTo produce the proteins needed for the cell to survive, the information in the DNA is converted to a mobile form known as messenger RNA, which exits the cell nucleus and binds to machines that convert RNAs into proteins in a process referred to as translation. Importantly, the RNA message can be altered at any point in its journey prior to translation. These alterations constitute changes to the chemical nature of the messenger RNA and modulate the ability of mRNAs to be converted into proteins and even lead to the production of proteins with different functionalities than those encoded by their original forms. Here we provide a conceptual framework for the integration of these mRNA maturation steps with translation with a focus on the proteins that escort these mRNAs through these steps and into the translation machines. We discuss the relevance to cancer and therapeutic strategies to target these in malignancy.The translation of RNA into protein is a dynamic process which is heavily regulated during normal cell physiology and can be dysregulated in human malignancies. Its dysregulation can impact selected groups of RNAs, modifying protein levels independently of transcription. Integral to their suitability for translation, RNAs undergo a series of maturation steps including the addition of the m7G cap on the 5′ end of RNAs, splicing, as well as cleavage and polyadenylation (CPA). Importantly, each of these steps can be coopted to modify the transcript signal. Factors that bind the m7G cap escort these RNAs through different steps of maturation and thus govern the physical nature of the final transcript product presented to the translation machinery. Here, we describe these steps and how the major m7G cap-binding factors in mammalian cells, the cap binding complex (CBC) and the eukaryotic translation initiation factor eIF4E, are positioned to chaperone transcripts through RNA maturation, nuclear export, and translation in a transcript-specific manner. To conceptualize a framework for the flow and integration of this genetic information, we discuss RNA maturation models and how these integrate with translation. Finally, we discuss how these processes can be coopted by cancer cells and means to target these in malignancy.
Highlights
The translation of RNA into protein is a dynamic process which is heavily regulated during normal cell physiology and can be dysregulated in human malignancies
The CTN RNA undergoes a first round of cleavage and polyadenylation (CPA), likely co-transcriptionally, but the polyadenylated mRNA remains stored in the nucleus until specific signaling events trigger the cleavage of another polyadenylation signal (PAS) within the CTN RNA to produce the CAT2 RNA, which is followed by poly(A) tail addition and is exported to the cytoplasm and translated into protein [53]
Translation can be regulated at many steps and has been recently reviewed [103,104,105]; here, we focus on the initiation step. eIF4E-dependent translation initiation is considered as the “reference” pathway in that regard
Summary
The translation of RNAs into proteins is a fundamental step in the conversion of DNA signals (in the form of coding transcripts) into their active form (proteins). The classic model is that CBC escorts RNAs in the nucleus as they undergo maturation steps that will define their function, transporting them to the cytoplasm where these RNAs are handed off to eIF4E for steady-state translation [14] (Figure 1). While eIF4E increased capping for some RNAs, it reduced the capping for others, suggesting there is a competition for limited resources (RNGTT, RAM, RNMT, SAM) so that eIF4E tips the balance to favor specific transcripts These studies revealed that in human cells the capping of specific RNAs at steady-state was lower than anticipated, positioning this as an important regulatory step in terms of the functionality of RNAs. eIF4E does not provide protection against decapping by directly binding to m7G caps of its target RNAs [15]. EIF4E increases capping for a subset of RNAs, likely containing specific RNA elements that imbue these RNAs with sensitivity to this process by recruiting factors such as RNMT to the transcripts
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