Comparative parallel analysis of RNA ends identifies mRNA substrates of a tRNA splicing endonuclease-initiated mRNA decay pathway

Eukaryotes share a conserved messenger RNA (mRNA) decay pathway in which bulk mRNA is degraded by exoribonucleases. In addition, it has become clear that more specialized mRNA decay pathways are initiated by endonucleolytic cleavage at particular sites. The transfer RNA (tRNA) splicing endonuclease...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 10; pp. 1 - 12
Main Authors Hurtig, Jennifer E., Steiger, Michelle A., Nagarajan, Vinay K., Li, Tao, Chao, Ti-Chun, Tsai, Kuang-Lei, van Hoof, Ambro
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 09.03.2021
Subjects
Amino acids
Biological Sciences
Cleavage
Decay
Endonuclease
Eukaryotes
Hypoplasia
Introns
Localization
Mitochondria
mRNA turnover
Mutation
Splicing
Substrates
Target recognition
Transfer RNA
tRNA
Yeast
Yeasts
endonuclease
mRNA degradation
tRNA splicing
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Summary:Eukaryotes share a conserved messenger RNA (mRNA) decay pathway in which bulk mRNA is degraded by exoribonucleases. In addition, it has become clear that more specialized mRNA decay pathways are initiated by endonucleolytic cleavage at particular sites. The transfer RNA (tRNA) splicing endonuclease (TSEN) has been studied for its ability to remove introns from pre-tRNAs. More recently it has been shown that single amino acid mutations in TSEN cause pontocerebellar hypoplasia. Other recent studies indicate that TSEN has other functions, but the nature of these functions has remained obscure. Here we show that yeast TSEN cleaves a specific subset of mRNAs that encode mitochondrial proteins, and that the cleavage sites are in part determined by their sequence. This provides an explanation for the counterintuitive mitochondrial localization of yeast TSEN. To identify these mRNA target sites, we developed a “comPARE” (comparative parallel analysis of RNA ends) bioinformatic approach that should be easily implemented and widely applicable to the study of endoribonucleases. The similarity of tRNA endonuclease-initiated decay to regulated IRE1-dependent decay of mRNA suggests that mRNA specificity by colocalization may be an important determinant for the degradation of localized mRNAs in a variety of eukaryotic cells.
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Edited by Roy Parker, University of Colorado Boulder, Boulder, CO, and approved January 25, 2021 (received for review September 29, 2020)
Author contributions: J.E.H., M.A.S., V.K.N., and A.v.H. designed research; J.E.H., M.A.S., V.K.N., T.L., T.-C.C., and K.-L.T. performed research; J.E.H., T.L., T.-C.C., and K.-L.T. contributed new reagents/analytic tools; J.E.H., M.A.S., and A.v.H. analyzed data; and J.E.H., M.A.S., V.K.N., T.L., T.-C.C., K.-L.T., and A.v.H. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2020429118