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首页> 外文期刊>PLoS Genetics >Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons
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Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons

机译：单个氨基酸取代的自然变异是对拓扑异构酶II毒物的生理反应的基础

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Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.
机译：许多化疗药物对一个患者至另一患者的疗效不同。了解这种差异的原因是朝着个性化治疗和改进现有药物迈出的关键一步。在这里，我们调查使用模型生物秀丽隐杆线虫对一组靶向拓扑异构酶II的抗肿瘤药物的敏感性。我们显示野生秀丽隐杆线虫菌株对这些药物的敏感性各不相同，并且我们使用无偏遗传方法来证明这种自然变异是由拓扑异构酶II（TOP-2）中的甲硫氨酸-谷氨酰胺取代所解释的。与极性谷氨酰胺相比，在该残基处存在非极性蛋氨酸会增加TOP-2及其毒性依托泊苷之间的疏水相互作用。我们假设这种稳定的相互作用导致包含蛋氨酸残基的菌株的基因组不稳定性增加。受此取代影响的残基从酵母到人类都是保守的，并且是两种人类拓扑异构酶II同工型（hTOPIIα中的蛋氨酸和hTOPIIβ中的谷氨酰胺）之间的少数差异之一。我们继续表明，两种人类拓扑异构酶同工型之间的氨基酸差异会影响拓扑异构酶II毒物在人类细胞系中的细胞毒性。这些结果解释了为什么hTOPIIα和hTOPIIβ受到各种毒物的不同影响，并证明秀丽隐杆线虫在理解药物反应的遗传学方面的效用。

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