The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans
The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans
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DOI：
10.1101/2021.12.06.471441
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Marzia Rizzo;Natthapon Soisangwan;J. Soetaert;Samuel Vega-Estévez;Anna Selmecki;A. Buscaino
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文献类型：
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作者：
Marzia Rizzo;Natthapon Soisangwan;J. Soetaert;Samuel Vega-Estévez;Anna Selmecki;A. Buscaino
压力诱导的微生物基因组不稳定性正在成为一种重要的调控机制，用于驱动快速和可逆的适应剧烈的环境变化。在白色念珠菌中，一种导致危及生命的感染的人类真菌病原体，基因组可塑性赋予增加的毒力和抗真菌药物抗性。揭示C.白念珠菌基因组可塑性是了解这种和其他微生物病原体如何建立危及生命的感染和对抗真菌药物产生耐药性的优先事项。我们鉴定了SUMO蛋白酶Ulp 2作为C.白念珠菌基因组的完整性通过遗传筛选。ULP 2的缺失导致对遗传毒性剂的超敏反应和增加的基因组不稳定性。基因组多样性的增加导致标准实验室生长条件下的适应性降低，但增强了对压力的适应性，使ulp 2 Δ/Δ细胞更有可能在抗真菌药物的存在下茁壮成长。全基因组测序表明ulp 2 Δ/Δ细胞通过发展染色体R和染色体I的节段性非整倍性来对抗抗真菌药物诱导的应激。我们证明，染色体内重复元件驱动形成复杂的新的基因型与适应能力。
Stress-induced genome instability in microbial organisms is emerging as a critical regulatory mechanism for driving rapid and reversible adaption to drastic environmental changes. In Candida albicans, a human fungal pathogen that causes life-threatening infections, genome plasticity confers increased virulence and antifungal drug resistance. Discovering the mechanisms regulating C. albicans genome plasticity is a priority to understand how this and other microbial pathogens establish life-threatening infections and develop resistance to antifungal drugs. We identified the SUMO protease Ulp2 as a critical regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to hypersensitivity to genotoxic agents and increased genome instability. This increased genome diversity causes reduced fitness under standard laboratory growth conditions but enhances adaptation to stress, making ulp2Δ/Δ cells more likely to thrive in the presence of antifungal drugs. Whole-genome sequencing indicates that ulp2Δ/Δ cells counteract antifungal drug-induced stress by developing segmental aneuploidies of chromosome R and chromosome I. We demonstrate that intrachromosomal repetitive elements drive the formation of complex novel genotypes with adaptive power.