CLK-2/TEL2 is a conserved component of the nonsense-mediated mRNA decay pathway.

Yanwu Guo,Cristina Tocchini,Rafal Ciosk

doi:10.1371/journal.pone.0244505

Abstract

Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.

Highlights

RNA-controlling mechanisms are important, among others, for removing aberrant transcripts, repressing viral RNAs, and regulating gene expression [1,2]
exon junction complexes (EJCs) located “downstream” from premature termination codons (PTCs), which remain associated with mRNA, facilitate the recruitment of a protein kinase, SMG1, which phosphorylates and activates a key Nonsense-mediated mRNA decay (NMD) factor, UPF1
We hypothesized that the short 3’ untranslated regions (3’UTRs) fragment, used in the R-1 reporter, may lack signals necessary for efficient pre-mRNA processing, giving rise to abnormal transcripts subjected to mRNA surveillance

Summary

Introduction

RNA-controlling mechanisms are important, among others, for removing aberrant transcripts, repressing viral RNAs, and regulating gene expression [1,2]. Nonsense-mediated mRNA decay is one of the best characterized, and evolutionarily conserved, surveillance mechanisms, which, by degrading mRNAs carrying premature termination codons (PTCs), prevents synthesis of truncated proteins [2]. During the first round of translation, exon-exon junction complexes (EJCs), deposited on mRNA during splicing, are removed from mRNA by elongating ribosomes. EJCs located “downstream” from PTCs, which remain associated with mRNA, facilitate the recruitment of a protein kinase, SMG1, which phosphorylates and activates a key NMD factor, UPF1. Activated UPF1 promotes the formation of a decay-inducing complex, eventually leading to the degradation of aberrant mRNA [2,3]

Methods

Results

Conclusion