Control of mRNA splicing by intragenic RNA activators of stress signaling: Potential implications for human disease

Raymond Kaempfer, Lena Ilan, Smadar Cohen-Chalamish, Orli Turgeman, Lise Sarah Namer, Farhat Osman

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations


A critical step in the cellular stress response is transient activation of the RNA-dependent protein kinase PKR by double-helical RNA, resulting in down-regulation of protein synthesis through phosphorylation of the α chain of translation initiation factor eIF2, a major PKR substrate. However, intragenic elements of 100-200 nucleotides in length within primary transcripts of cellular genes, exemplified by the tumor necrosis factor (TNF)-α gene and fetal and adult globin genes, are capable of forming RNA structures that potently activate PKR and thereby strongly enhance mRNA splicing efficiency. By inducing nuclear eIF2α phosphorylation, these PKR activator elements enable highly efficient early spliceosome assembly yet do not impair translation of the mature spliced mRNA. The TNF-α RNA activator of PKR folds into a compact pseudoknot that is highly conserved within the phylogeny. Upon excision of β-globin first intron, the RNA activator of PKR, located in exon 1, is silenced through strand displacement by a short sequence within exon 2, restricting thereby the ability to activate PKR to the splicing process without impeding subsequent synthesis of β-globin essential for survival. This activator/silencer mechanism likewise controls splicing of α-globin pre-mRNA, but the exonic locations of PKR activator and silencer sequences are reversed, demonstrating evolutionary flexibility. Impaired splicing efficiency may underlie numerous human β-thalassemia mutations that map to the β-globin RNA activator of PKR or its silencer. Even where such mutations change the encoded amino acid sequence during subsequent translation, they carry the potential of first impairing PKR-dependent mRNA splicing or shutoff of PKR activation needed for optimal translation.

Original languageEnglish
Article number464
JournalFrontiers in Genetics
Issue numberMAY
StatePublished - 2019
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by United States Congressionally Directed Medical Research Programs award (W81XWH-17-1-0647).

Publisher Copyright:
Copyright © 2019 Kaempfer, Ilan, Cohen-Chalamish, Turgeman, Namer and Osman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


  • Activation of PKR
  • EIF2α phosphorylation
  • Human β-thalassemia mutations
  • Intragenic RNA activators of PKR
  • PKR silencer elements
  • TNF-α gene
  • mRNA splicing control
  • β-globin gene


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