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细胞中 DNA 修复内切酶缺失的成分的化学-遗传相互作用似乎与液泡破坏有关。

Chemical-Genetic Interactions of Constituents in Cells Deficient for the DNA Repair Endonuclease Appear Linked to Vacuolar Disruption.

机构信息

Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

出版信息

Molecules. 2021 Feb 24;26(5):1207. doi: 10.3390/molecules26051207.

DOI:10.3390/molecules26051207
PMID:33668176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7956252/
Abstract

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for extracts to limit proliferation and promote an apoptosis-like event in deleted yeast was not elucidated. Our current analysis has revealed that extracts have the capacity to promote mutations in ∆ cells. In addition, the effects of extracts on ∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from identified a chemical-genetic interaction between bacopasaponin C and ∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.

摘要

结直肠癌是一种常见的癌症,DNA 修复内切酶 XPF(着色性干皮病互补组 F)表达降低与结直肠癌有关。先前发现,在缺乏 Rad1p(人类 XPF 的结构和功能同源物)的结直肠癌细胞模型中, 提取物表现出化学遗传合成致死效应。然而, 提取物在缺失酵母中限制增殖并促进类似凋亡事件的机制尚未阐明。我们目前的分析表明, 提取物具有促进 ∆ 细胞突变的能力。此外, 提取物对 ∆ 酵母的影响与液泡的破坏有关,类似于哺乳动物溶酶体。酵母中 的缺失使细胞对液泡破坏和蛋白酶释放的影响敏感。增加的 DNA 突变和液泡内容物的释放的联合作用似乎诱导了依赖于元半胱天冬酶 Yca1p 的类似凋亡的事件。 提取物的毒性与固醇含量有关,表明皂苷可能参与限制酵母细胞的增殖。对 中的主要成分的分析确定了 Bacopasaponin C 与 ∆ 酵母之间的化学遗传相互作用。Bacopasaponin C 可能具有作为药物候选物的潜力,或作为开发用于治疗结直肠癌的类似物的模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/693629f8509e/molecules-26-01207-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/34b6e6ba8ecb/molecules-26-01207-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/daf88ef7e918/molecules-26-01207-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/53a09474cdee/molecules-26-01207-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/1418de6c672d/molecules-26-01207-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/17db13c4c84f/molecules-26-01207-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/de41b69d09b8/molecules-26-01207-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/bcfbc6377af0/molecules-26-01207-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/b943cf3087a1/molecules-26-01207-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/e335fc78c656/molecules-26-01207-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/4784741d3be9/molecules-26-01207-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/693629f8509e/molecules-26-01207-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/34b6e6ba8ecb/molecules-26-01207-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/daf88ef7e918/molecules-26-01207-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/53a09474cdee/molecules-26-01207-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/1418de6c672d/molecules-26-01207-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/17db13c4c84f/molecules-26-01207-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/de41b69d09b8/molecules-26-01207-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/bcfbc6377af0/molecules-26-01207-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/b943cf3087a1/molecules-26-01207-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/e335fc78c656/molecules-26-01207-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/4784741d3be9/molecules-26-01207-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a034/7956252/693629f8509e/molecules-26-01207-g011.jpg

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The A-Like Faker Assay for Measuring Yeast Chromosome III Stability.用于测量酵母Ⅲ号染色体稳定性的A类伪造检测法
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Cancer Statistics, 2017.
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Differential Inhibition of Water and Ion Channel Activities of Mammalian Aquaporin-1 by Two Structurally Related Bacopaside Compounds Derived from the Medicinal Plant Bacopa monnieri.两种源自药用植物假马齿苋的结构相关的假马齿苋皂苷化合物对哺乳动物水通道蛋白-1水和离子通道活性的差异抑制作用
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