PUBLICATION

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

Authors
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.
ID
ZDB-PUB-180209-5
Date
2018
Source
Disease models & mechanisms   11(2): (Journal)
Registered Authors
Bowman, Teresa, Jette, Cicely A., Sorrells, Shelly, Stewart, Rodney A., Toruno, Cristhian, Truong, Harold
Keywords
Apoptosis, Neurons, R-loops, Radiation, Splicing, Zebrafish
MeSH Terms
  • Apoptosis*/radiation effects
  • Animals
  • RNA Splicing/genetics
  • RNA Splicing/radiation effects
  • Neurons/cytology*
  • Neurons/metabolism*
  • Neurons/radiation effects
  • Genes, Essential
  • Nucleic Acid Conformation*
  • Spliceosomes/metabolism*
  • DNA Damage*
  • DNA Breaks, Double-Stranded
  • Cytoprotection*/radiation effects
  • Radiation Tolerance/genetics
  • Radiation Tolerance/radiation effects
  • Zebrafish Proteins/metabolism
  • Mutation/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Radiation, Ionizing
(all 21)
PubMed
29419415 Full text @ Dis. Model. Mech.
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.
Genes / Markers
Figures
Figure Gallery (6 images)
Show all Figures
Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
tp53hspa8hi138Tg (AB)standard conditionsPrim-15WB
tp53plrg1hi3174aTg (AB)standard conditionsPrim-15WB
tp53sf3b1hi3394aTg/hi3394aTg (AB)standard conditionsPrim-15WB
tp53yju2zd1000/zd1000 (AB)standard conditionsPrim-15WB
1 - 4 of 4
Show
Phenotype
Fish Conditions Stage Phenotype Figure
AB + MO1-plrg1electromagnetic radiationPrim-5
AB + MO1-plrg1electromagnetic radiationPrim-5
hspa8hi138Tg (AB)standard conditionsPrim-15
plrg1hi3174aTg (AB)standard conditionsPrim-15
plrg1hi3174aTg (AB)standard conditionsPrim-15
sf3b1hi3394aTg/hi3394aTg (AB)standard conditionsPrim-5
sf3b1hi3394aTg/hi3394aTg (AB)standard conditionsPrim-5
sf3b1hi3394aTg/hi3394aTg (AB)standard conditionsPrim-15
sf3b1hi3394aTg/hi3394aTg (AB)standard conditionsPrim-15
sf3b1hi3394aTg/hi3394aTg (AB)electromagnetic radiationPrim-5
1 - 10 of 31
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi138TgTransgenic Insertion
hi1779TgTransgenic Insertion
hi3174aTgTransgenic Insertion
hi3394aTgTransgenic Insertion
hi3678TgTransgenic Insertion
hi3820bTgTransgenic Insertion
zd1000
    		Point Mutation
    zd1006
      		Point Mutation
      zd1009TgTransgenic Insertion
        zdf1
          		Point Mutation
          1 - 10 of 10
          Show
          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          plrg1MO1-plrg1MRPHLNO
          1 - 1 of 1
          Show
          Fish
          Fish
          AB + MO1-plrg1
          hspa8hi138Tg (AB)
          plrg1hi3174aTg (AB)
          sf3b1hi3394aTg/hi3394aTg (AB)
          sf3b1hi3394aTg/hi3394aTg; zd1009Tg (AB)
          sfpqhi1779Tg/hi1779Tg (AB)
          tp53zdf1/zdf1; plrg1hi3174aTg (AB)
          tp53zdf1/zdf1; sf3b1hi3394aTg/hi3394aTg (AB)
          tp53zdf1/zdf1; yju2zd1000/zd1000 (AB)
          txnl4azd1006/zd1006 (AB)
          1 - 10 of 11
          Show
          Antibodies
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          GFPEFGGFP
          1 - 1 of 1
          Show
          Mapping
          No data available
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          Citation
          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).