Cells use messenger RNAs (mRNAs) to ensure the accurate dissemination of genetic information encoded by DNA. Given that mRNAs largely direct the synthesis of a critical effector of cellular phenotype, i.e., proteins, tight regulation of both the quality and quantity of mRNA is a prerequisite for effective cellular homeostasis. Here, we review nonsense-mediated mRNA decay (NMD), which is the best-characterized posttranscriptional quality control mechanism that cells have evolved in their cytoplasm to ensure transcriptome fidelity. We use protein quality control as a conceptual framework to organize what is known about NMD, highlighting overarching similarities between these two polymer quality control pathways, where the protein quality control and NMD pathways intersect, and how protein quality control can suggest new avenues for research into mRNA quality control.
In mammals, two different messenger ribonucleoproteins (mRNPs) serve as templates for protein synthesis. Newly synthesized CBP80‐CBP20 (CBC)‐bound mRNPs initially undergo a pioneer round of translation (Maquat et al., 2010). One purpose of this round is to ensure the quality of gene expression, as exemplified by nonsense‐mediated mRNA decay (NMD). NMD functions to eliminate mRNAs that prematurely terminate translation, and also contributes to proper gene control, and it targets CBC‐bound mRNPs (Sato et al., 2008; Isken et al., 2008). CBC‐bound mRNPs are remodeled to eIF4E‐bound mRNPs as a consequence of the pioneer round of translation and also independently of translation (Sato & Maquat, 2009). eIF4E‐bound mRNPs support the bulk of cellular protein synthesis and are the primary targets of mRNA decay mechanisms that conditionally regulate gene expression, such as Staufen1‐mediated mRNA decay (SMD) (Gong et al., 2009). Mechanistic aspects of NMD will be discussed, including how CBP80, which is acquired by the 5′ caps of newly synthesized transcripts, promotes NMD at multiple steps by promoting specific mRNP rearrangements (Hwang et al., 2010). Mechanistic aspects of SMD will also be described, including how Staufen1‐binding sites form not only by intramolecular base‐pairing within an mRNA 3′‐untranslated region but also by intermolecular basepairing between the Alu element of an mRNA 3‐untranslated region and a partially complementary Alu element within a long noncoding RNA (Gong & Maquat, 2011).
The largely nuclear cap-binding complex (CBC) binds to the 5 ′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. While influence of the CBC can extend into the cytoplasm, here we review the roles of the CBC in the nucleus, with a focus on protein-coding genes. We discuss differences between CBC function in yeast and mammals, covering the steps of transcription initiation, release of RNAPII from pausing, transcription elongation, cotranscriptional pre-mRNA splicing, transcription termination, and consequences of spurious transcription. We describe parameters known to control the binding of generic or gene-specific cofactors that regulate CBC activities depending on the process(es) targeted, illustrating how the CBC is an ever-changing choreographer of gene expression.The nuclear cap-binding complex (CBC), which is a heterodimer conserved from Saccharomyces cerevisiae to Homo sapiens, is composed of two cap-binding proteins (CBPs). CBP20 directly binds the m 7 G cap at the 5 ′ end of RNA polymerase II (RNAPII)-synthesized transcripts, while CBP80 stabilizes the binding of CBP20 to the cap and serves as an interaction platform for numerous factors that control virtually every step of gene expression (Gonatopoulos-Pournatzis and Cowling 2014; Müller-McNicoll and Neugebauer 2014). RNAPII-synthesized transcripts bound by the CBC include precursor and processed mRNAs, long noncoding RNAs (lncRNAs), promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), immature small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs) of intergenic origin, and primary-micro-RNAs (pri-miRNAs). Whereas our lab discovered and con-tributed to elucidating the role of the CBC in the cytoplasm during the pioneer round of translation and nonsense-mediated mRNA decay (NMD) (for review, see Maquat et al. 2010;Ryu and Kim 2017;Kurosaki et al. 2019), our current research focuses on the role of the CBC during gene transcription by RNAPII (Cho et al. 2018). Here, we review known roles of the CBC in the nucleus during the transcription of genes that encode proteins, stitching together past studies from diverse groups to describe the continuum of CBC-mediated checks and balances in eukaryotic cells. Chromatin-associated steps in the synthesis and processing of protein-coding transcriptsThe transcription of eukaryotic protein-coding genes is a stepwise process that can be divided into fundamental stages, all of which are regulated by the CBC: preinitiation complex assembly, transcription initiation, promoterproximal pausing, processive transcription elongation, and transcription termination coupled to pre-mRNA 3 ′ end processing. The process of pre-mRNA splicing, being largely cotranscriptional, is also presented in this review. Preinitiation complex assemblyThe first step of gene transcription is assembly at the core promoter of a preinitiation complex (PIC) composed of RNAPII and general transcription factors (GTFs). ...
In mammalian cells, two different messenger ribonucleoproteins (mRNPs) serve as templates for protein synthesis. Newly synthesized mRNPs bound by the cap-binding protein heterodimer CBP80-CBP20 (CBC) initially undergo a pioneer round of translation. One purpose of this round of translation is to ensure the quality of gene expression, as exemplified by nonsense-mediated messenger RNA (mRNA) decay (NMD). NMD largely functions to eliminate mRNAs that prematurely terminate translation, although NMD also contributes to proper gene control, and it targets CBC-bound mRNPs. CBC-bound mRNPs are remodeled to eukaryotic translation initiation factor (eIF)4E-bound mRNPs in steps that (1) are a consequence of the pioneer round of translation and (2) occur independently of translation. Rather than supporting NMD, eIF4E-bound mRNPs provide for the bulk of cellular protein synthesis and are the primary targets of mRNA decay mechanisms that conditionally regulate gene expression. Here, we overview cellular processes by which CBC-bound mRNPs are remodeled to eIF4E-bound mRNPs. We also describe the molecular movements of certain factors during NMD in view of the influential role of CBP80.
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