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

被引:18
作者
Tama, Annie S. [1 ,2 ]
Sihota, Tianna S. [1 ]
Milbury, Karissa L. [1 ]
Zhang, Anni [1 ]
Mathew, Veena [1 ]
Stirling, Peter C. [1 ,2 ]
机构
[1] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
[2] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
MESSENGER-RNA EXPORT; CELL-CYCLE ARREST; SACCHAROMYCES-CEREVISIAE; DNA-DAMAGE; R-LOOP; RNA/DNA HYBRIDS; MUTATIONS; TRANSCRIPTION; INTRONS; REVEALS;
D O I
10.1091/mbc.E18-07-0439
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 a-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.
引用
收藏
页码:191 / 200
页数:10
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