Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis

Shelly Sorrells, Sara Nik, Mattie Casey, Rosannah C. Cameron, Harold Truong, Cristhian Toruno, Michelle Gulfo, Albert Lowe, Cicely Jette, Rodney A. Stewart, Teresa V. Bowman

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

RNA splicing factors are essential for the viability of all eukaryotic cells; however, in metazoans some cell types are exquisitely sensitive to disruption of splicing factors. Neuronal cells represent one such cell type, and defects in RNA splicing factors can lead to neurodegenerative diseases. The basis for this tissue selectivity is not well understood owing to difficulties in analyzing the consequences of splicing factor defects in whole-animal systems. Here, we use zebrafish mutants to show that loss of spliceosomal components, including splicing factor 3b, subunit 1 (sf3b1), causes increased DNA double-strand breaks and apoptosis in embryonic neurons. Moreover, these mutants show a concomitant accumulation of R-loops, which are non-canonical nucleic acid structures that promote genomic instability. Dampening R-loop formation by conditional induction of ribonuclease H1 in sf3b1 mutants reduced neuronal DNA damage and apoptosis. These findings show that splicing factor dysfunction leads to R-loop accumulation and DNA damage that sensitizes embryonic neurons to apoptosis. Our results suggest that diseases associated with splicing factor mutations could be susceptible to treatments that modulate R-loop levels.

Original languageEnglish (US)
JournalDisease models & mechanisms
Volume11
Issue number2
DOIs
StatePublished - Feb 26 2018

Keywords

  • Apoptosis
  • Neurons
  • R-loops
  • Radiation
  • Splicing
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Sorrells, S., Nik, S., Casey, M., Cameron, R. C., Truong, H., Toruno, C., Gulfo, M., Lowe, A., Jette, C., Stewart, R. A., & Bowman, T. V. (2018). Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis. Disease models & mechanisms, 11(2). https://doi.org/10.1242/dmm.031583