Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Mol Biol Cell. 2019 Jan 15;30(2):191-200. doi: 10.1091/mbc.E18-07-0439. Epub 2018 Nov 21.
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.
RNA 加工突变体广泛参与基因组稳定性，但机制联系往往不清楚。已经出现了两种主要模型：一种涉及改变基因表达，扰乱其他基因组维持因子，另一种涉及称为 R 环的遗传毒性 DNA:RNA 杂交体，破坏 DNA 复制。在这里，我们描述了酵母剪接因子突变体中的基因组不稳定性表型，发现有丝分裂缺陷，以及在某些情况下 R 环积累，是基因组不稳定的原因。在这两种情况下，基因表达的改变而不是顺式作用，可能导致不稳定。纺锤体装配检查点蛋白 Mad1 的缺失会加剧剪接突变体的基因组不稳定性。此外，从 TUB1 基因中去除内含子可以恢复基因组完整性。因此，剪接体条件突变体中转录组的不同穿透率和选择性效应可能导致一系列表型，包括基因组不稳定性的多种途径。
