Loss of the SUMO Protease Ulp2 Triggers a Specific Multi-Chromosome Aneuploidy

Post-translational protein modification by the small ubiquitin-related modifier (SUMO) protein regulates numerous cellular pathways, including transcription, cell division and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. To investigate changes to the transcriptome of cells lacking Ulp2, whole-genome RNA sequencing (RNA-seq) was employed. Unexpectedly, ulp2Δ cells display a general two-fold increase in transcript levels across two particular chromosomes, Chromosome I (ChrI) and Chromosome XII (ChrXII). Quantification of relative DNA levels showed that ChrI and ChrXII are present at twice their normal copy number in ulp2Δ cells. This double disomy occurs in mutants in multiple genetic backgrounds and does not require passage through meiosis. An abnormal number of chromosomes in a cell, termed aneuploidy, is usually deleterious. However, development of specific aneuploidies allows rapid adaptation to cellular stresses in yeast and other species, and aneuploidy characterizes most tumors. Extra copies of ChrI and ChrXII appear quickly following loss of active Ulp2, suggesting aneuploidy is an adaptive mechanism in cells lacking the functional SUMO protease. The specific aneuploidy in ulp2Δ cells highlights a unique example of a homogeneous, multi-chromosome aneuploidy in response to mutation of a single gene.小泛素相关修饰物（small ubiquitin-related modifier, SUMO）介导的蛋白质翻译后修饰，调控包括转录、细胞分裂与基因组维持在内的诸多细胞通路。SUMO蛋白酶Ulp2可在酿酒酵母（budding yeast）中调控诸多依赖SUMO的生物学过程。为探究Ulp2缺失细胞的转录组变化，本研究采用了全基因组RNA测序（whole-genome RNA sequencing, RNA-seq）技术。出乎意料的是，ulp2缺失（ulp2Δ）细胞在两条特定染色体——一号染色体（Chromosome I, ChrI）与十二号染色体（Chromosome XII, ChrXII）上的转录本水平普遍升高两倍。相对DNA水平定量分析显示，ulp2Δ细胞中ChrI与ChrXII的拷贝数为正常水平的两倍。这种双染色体双体现象可在多种遗传背景的突变体中出现，且无需经过减数分裂过程。细胞内染色体数目异常被称为非整倍体（aneuploidy），通常具有有害性。然而，特定非整倍体的形成可帮助酵母及其他物种快速适应细胞应激，且绝大多数肿瘤均存在非整倍体特征。在功能性Ulp2缺失后，ChrI与ChrXII的额外拷贝会快速出现，这表明非整倍体是缺失功能性SUMO蛋白酶的细胞的一种适应性机制。ulp2Δ细胞中出现的特异性非整倍体，为单基因突变引发的均一化多染色体非整倍体提供了一个独特的研究范例。