Stalled spliceosomes are a signal for RNAi-mediated genome defense

Phillip A. Dumesic, Prashanthi Natarajan, Changbin Chen, Ines A. Drinnenberg, Benjamin J. Schiller, James Thompson, James J. Moresco, John R. Yates, David P. Bartel, Hiten D. Madhani

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

Using the yeast Cryptococcus neoformans, we describe a mechanism by which transposons are initially targeted for RNAi-mediated genome defense. We show that intron-containing mRNA precursors template siRNA synthesis. We identify a Spliceosome-Coupled And Nuclear RNAi (SCANR) complex required for siRNA synthesis and demonstrate that it physically associates with the spliceosome. We find that RNAi target transcripts are distinguished by suboptimal introns and abnormally high occupancy on spliceosomes. Functional investigations demonstrate that the stalling of mRNA precursors on spliceosomes is required for siRNA accumulation. Lariat debranching enzyme is also necessary for siRNA production, suggesting a requirement for processing of stalled splicing intermediates. We propose that recognition of mRNA precursors by the SCANR complex is in kinetic competition with splicing, thereby promoting siRNA production from transposon transcripts stalled on spliceosomes. Disparity in the strength of expression signals encoded by transposons versus host genes offers an avenue for the evolution of genome defense.

Original languageEnglish (US)
Pages (from-to)957-968
Number of pages12
JournalCell
Volume152
Issue number5
DOIs
StatePublished - Feb 28 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dumesic, P. A., Natarajan, P., Chen, C., Drinnenberg, I. A., Schiller, B. J., Thompson, J., Moresco, J. J., Yates, J. R., Bartel, D. P., & Madhani, H. D. (2013). Stalled spliceosomes are a signal for RNAi-mediated genome defense. Cell, 152(5), 957-968. https://doi.org/10.1016/j.cell.2013.01.046