Structural insights into the exon junction complex

Hir, Hervé Le; Andersen, G.R.

doi:10.1016/j.sbi.2007.11.002

Cited by 95 publications

(48 citation statements)

References 36 publications

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“…This feedback regulatory response was specific, as the transcript encoding the uniquely weak NMD factor, UPF3A (Kunz et al, 2006; Chan et al, 2009), did not significantly increase in level in response to NMD perturbation, suggesting that it is not feedback regulated (Figure 1A). Also not significantly feedback regulated were the transcripts encoding the core exon-junction complex (EJC) factors (i.e.,Y14, MAGOH, CASC3, and eIF4A3), which all promote mammalian NMD but are not essential for NMD (Figure 1A) (Le Hir and Andersen, 2008; Chan et al, 2009; Rebbapragada and Lykke-Andersen, 2009). As an independent test of feedback regulation by NMD, we treated HeLa cells with the protein synthesis blocker cycloheximide (CHX), a potent inhibitor of the NMD pathway (Carter et al, 1996; Amrani et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

RNA Homeostasis Governed by Cell Type-Specific and Branched Feedback Loops Acting on NMD

et al. 2011

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SUMMARY Nonsense-mediated mRNA decay (NMD) is a conserved RNA decay pathway that degrades aberrant mRNAs and directly regulates many normal mRNAs. This dual role for NMD raises the possibility that its magnitude is buffered to prevent the potentially catastrophic alterations in gene expression that would otherwise occur if NMD were perturbed by environmental or genetic insults. In support of this, here we report the existence of a negative feedback regulatory network that directly acts on seven NMD factors. Feedback regulation is conferred by different branches of the NMD pathway in a cell type-specific and developmentally regulated manner. We identify feedback-regulated NMD factors that are rate limiting for NMD and demonstrate that reversal of feedback regulation in response to NMD perturbation is crucial for maintaining NMD. Together, our results suggest the existence of an intricate feedback network that maintains both RNA surveillance and the homeostasis of normal gene expression in mammalian cells.

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Section: Resultsmentioning

confidence: 99%

RNA Homeostasis Governed by Cell Type-Specific and Branched Feedback Loops Acting on NMD

et al. 2011

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“…MAGOH, eIF4A3, Y14, and MLN51 form the core of the EJC that binds to sequences 20 to 24 nucleotides upstream of exon-exon boundaries (43,44). The EJC is recruited to transcripts by the intron-binding protein IBP160 (45) and deposited on the RNA via eIF4A3 prior to exon ligation during splicing (46,47).…”

Section: Resultsmentioning

confidence: 99%

“…The EJC has been implicated in transcription, nuclear mRNA export, nonsense-mediated decay (NMD), and enhanced translation (48)(49)(50)(51). It also acts as a general scaffold for a variety of factors implicated in cotranscriptional mRNA processing, especially 3= end formation (e.g., UPF2, UPF3, and RNPS1) (44). SRSFs are characterized by a common domain organization: one or two N-terminal RNA recognition motifs (RRMs) and a C-terminal Arg-Ser-rich domain (RS domain).…”

Section: Resultsmentioning

confidence: 99%

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Eifler

Shao

Bartholomeeusen

et al. 2015

Molecular and Cellular Biology

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Transcriptional cyclin-dependent kinases (CDKs) regulate RNA polymerase II initiation and elongation as well as cotranscriptional mRNA processing. In this report, we describe an important role for CDK12 in the epidermal growth factor (EGF)-induced c-FOS proto-oncogene expression in mammalian cells. This kinase was found in the exon junction complexes (EJC) together with SR proteins and was thus recruited to RNA polymerase II. In cells depleted of CDK12 or eukaryotic translation initiation factor 4A3 (eIF4A3) from the EJC, EGF induced fewer c-FOS transcripts. In these cells, phosphorylation of serines at position 2 in the C-terminal domain (CTD) of RNA polymerase II, as well as levels of cleavage-stimulating factor 64 (Cstf64) and 73-kDa subunit of cleavage and polyadenylation specificity factor (CPSF73), was reduced at the c-FOS gene. These effects impaired 3′ end processing of c-FOS transcripts. Mutant CDK12 proteins lacking their Arg-Ser-rich (RS) domain or just the RS domain alone acted as dominant negative proteins. Thus, CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts.

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“…Four proteins form the EJC core: the constitutive heterodimer Magoh/Y14, the DEAD-box RNA helicase eIF4A3 (eukaryotic initiation factor 4AIII), and MLN51 (metastatic lymph node 51), also known as CASC3 and Barentsz (BTZ; Ballut et al , 2005; Tange et al , 2005). EJC cores accompany mRNAs to the cytoplasm, where the translation machinery removes them from open reading frames (Le Hir et al , 2001b; Dostie and Dreyfuss, 2002; Lejeune et al , 2002; Gehring et al , 2009b); they constitute binding platforms for peripheral factors that dynamically associate and dissociate during mRNA travel (Le Hir and Andersen, 2008; Buchwald et al , 2010; Bono and Gehring, 2011). Several functions are attributed to this complex, in both the nucleus and the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%