Agyare-Tabbi Michelle R, Uthayakumar Deeva, Francis Desiree, Maroc Laetitia, Grant Chris, McQueen Peter, Westmacott Garret, Shaker Hajer, Skulska Iwona, Gagnon-Arsenault Isabelle, Boisvert Jonathan, Landry Christian R, Shapiro Rebecca S
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1H 5N4 Canada.
Department of Immunology, University of Toronto, Toronto, ON M5R 0A3 Canada.
NPJ Antimicrob Resist. 2024;2(1):42. doi: 10.1038/s44259-024-00057-0. Epub 2024 Nov 29.
Antimicrobial-induced DNA damage, and subsequent repair via upregulation of DNA repair factors, including error-prone translesion polymerases, can lead to the increased accumulation of mutations in the microbial genome, and ultimately increased risk of acquired mutations associated with antimicrobial resistance. While this phenotype is well described in bacterial species, it is less thoroughly investigated amongst microbial fungi. Here, we monitor DNA damage induced by antifungal agents in the fungal pathogen , and find that commonly used antifungal drugs are able to induce DNA damage, leading to the upregulation of transcripts encoding predicted error-prone polymerases and related factors. We focus on , encoding a putative error-prone polymerase, and find that while deleting this gene in leads to increased sensitivity to DNA damage, it also unexpectedly renders cells more likely to incur mutations and evolve resistance to antifungal agents. We further find that deletion of leads to a significant depletion in the uncharacterized protein Shm1, which itself plays a role in fungal mutagenesis. Together, this work lends new insight into previously uncharacterized factors with important roles in the DNA damage response, mutagenesis, and the evolution of antifungal drug resistance.
抗菌药物诱导的DNA损伤,以及随后通过上调DNA修复因子(包括易出错的跨损伤聚合酶)进行的修复,可导致微生物基因组中突变的积累增加,并最终增加与抗菌药物耐药性相关的获得性突变风险。虽然这种表型在细菌物种中已有充分描述,但在微生物真菌中研究较少。在此,我们监测了抗真菌药物在真菌病原体中诱导的DNA损伤,发现常用的抗真菌药物能够诱导DNA损伤,导致编码预测的易出错聚合酶和相关因子的转录本上调。我们重点研究了编码一种假定的易出错聚合酶的基因,发现虽然在该基因中删除该基因会导致对DNA损伤的敏感性增加,但它也意外地使细胞更容易发生突变并对抗真菌药物产生耐药性。我们进一步发现,删除该基因会导致未表征的蛋白质Shm1显著耗竭,而Shm1本身在真菌诱变中发挥作用。总之,这项工作为以前未表征的因素提供了新的见解,这些因素在DNA损伤反应、诱变和抗真菌药物耐药性的演变中具有重要作用。