Uncovering Bleomycin-Induced Genomic Alterations and Underlying Mechanisms in the Yeast Saccharomyces cerevisiae
| Autor: | Yang Sui, Ke-Jing Li, Ying-Xuan Zhu, Ke Zhang, Huan Sheng, Dao-Qiong Zheng, Yu-Ting Wang |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Applied and Environmental Microbiology. 88 |
| ISSN: | 1098-5336 0099-2240 |
| DOI: | 10.1128/aem.01703-21 |
| Popis: | Bleomycin (BLM) is a widely used chemotherapeutic drug. BLM-treated cells showed an elevated rate of mutations, but the underlying mechanisms remained unclear. In this study, the global genomic alterations in BLM-treated cells were explored in the yeast Saccharomyces cerevisiae. Using genetic assay and whole-genome sequencing, we found that the mutation rate could be greatly elevated in S. cerevisiae cells that underwent ZeocinTM (a BLM member) treatment. One-base deletion and T to G substitution at the 5'-GT-3' motif was the most striking signature of ZeocinTM-induced mutations. This was mainly the result of translesion DNA synthesis involving Rev1 and polymerase ζ. ZeocinTM treatment led to the frequent loss of heterozygosity and chromosomal rearrangements in the diploid strains. The breakpoints of recombination events were significantly associated with certain chromosomal elements. Lastly, we identified multiple genomic alterations that contributed to BLM resistance in the ZeocinTM-treated mutants. Overall, this study provides new insights into the genotoxicity and evolutional effects of BLM. Importance Bleomycin is an antitumor antibiotic that can mutate genomic DNA. Using yeast models in combination with genome sequencing, the mutational signatures of ZeocinTM (a member of the bleomycin family) are disclosed. Translesion-synthesis polymerases are crucial for the viability of ZeocinTM-treated yeast cells at the sacrifice of a higher mutation rate. We also confirmed that multiple genomic alterations were associated with the improved resistance to ZeocinTM, providing novel insights into how bleomycin resistance is developed in cells. |
| Databáze: | OpenAIRE |
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