Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis
| Autor: | Harold Truong, Michelle Gulfo, Rosannah C. Cameron, Shelly Sorrells, Sara Nik, Rodney A. Stewart, Cicely A. Jette, Teresa V. Bowman, Mattie J. Casey, Cristhian Toruno, Albert Lowe |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genome instability RNA Splicing Factors DNA damage R-loop RNA Splicing Neuroscience (miscellaneous) Medicine (miscellaneous) lcsh:Medicine Apoptosis Splicing Radiation Tolerance General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Splicing factor Immunology and Microbiology (miscellaneous) Radiation Ionizing lcsh:Pathology Animals DNA Breaks Double-Stranded Zebrafish Neurons Genes Essential Radiation biology lcsh:R R-loops Zebrafish Proteins biology.organism_classification Zebra 3. Good health Cell biology 030104 developmental biology Cytoprotection RNA splicing Mutation Nucleic acid Spliceosomes Nucleic Acid Conformation Tumor Suppressor Protein p53 DNA Damage Research Article lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 11, Iss 2 (2018) Disease Models & Mechanisms |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | 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. Summary: Loss of RNA splicing factors causes R-loop accumulation and DNA damage in embryonic neurons, sensitizing them to radiation-induced cell death. These findings suggest that diseased cells with mutations in splicing factors are vulnerable to radiotherapy. |
| Databáze: | OpenAIRE |
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