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Selective defects in gene expression control genome instability in yeast splicing mutants

RNA processing mutants have been broadly implicated in genome stability, but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors and another in which genotoxic DNA:RNA hybrids, called R-loops...

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Autores principales: Tam, Annie S., Sihota, Tianna S., Milbury, Karissa L., Zhang, Anni, Mathew, Veena, Stirling, Peter C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589566/
https://www.ncbi.nlm.nih.gov/pubmed/30462576
http://dx.doi.org/10.1091/mbc.E18-07-0439
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author Tam, Annie S.
Sihota, Tianna S.
Milbury, Karissa L.
Zhang, Anni
Mathew, Veena
Stirling, Peter C.
author_facet Tam, Annie S.
Sihota, Tianna S.
Milbury, Karissa L.
Zhang, Anni
Mathew, Veena
Stirling, Peter C.
author_sort Tam, Annie S.
collection PubMed
description RNA processing mutants have been broadly implicated in genome stability, but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. In both cases, alterations in gene expression, rather than direct cis effects, are likely to contribute to instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, differing penetrance and selective effects on the transcriptome can lead to a range of phenotypes in conditional mutants of the spliceosome, including multiple routes to genome instability.
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spelling pubmed-65895662019-06-28 Selective defects in gene expression control genome instability in yeast splicing mutants Tam, Annie S. Sihota, Tianna S. Milbury, Karissa L. Zhang, Anni Mathew, Veena Stirling, Peter C. Mol Biol Cell Brief Reports RNA processing mutants have been broadly implicated in genome stability, but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. In both cases, alterations in gene expression, rather than direct cis effects, are likely to contribute to instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, differing penetrance and selective effects on the transcriptome can lead to a range of phenotypes in conditional mutants of the spliceosome, including multiple routes to genome instability. The American Society for Cell Biology 2019-01-15 /pmc/articles/PMC6589566/ /pubmed/30462576 http://dx.doi.org/10.1091/mbc.E18-07-0439 Text en © 2019 Tam et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Brief Reports
Tam, Annie S.
Sihota, Tianna S.
Milbury, Karissa L.
Zhang, Anni
Mathew, Veena
Stirling, Peter C.
Selective defects in gene expression control genome instability in yeast splicing mutants
title Selective defects in gene expression control genome instability in yeast splicing mutants
title_full Selective defects in gene expression control genome instability in yeast splicing mutants
title_fullStr Selective defects in gene expression control genome instability in yeast splicing mutants
title_full_unstemmed Selective defects in gene expression control genome instability in yeast splicing mutants
title_short Selective defects in gene expression control genome instability in yeast splicing mutants
title_sort selective defects in gene expression control genome instability in yeast splicing mutants
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589566/
https://www.ncbi.nlm.nih.gov/pubmed/30462576
http://dx.doi.org/10.1091/mbc.E18-07-0439
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