在微卫星不稳定的癌症中,WRN旋酶是一种合成致命的目标
Edmond M Chan1,2, Tsukasa Shibue1, James M McFarland1
1Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nature
|April 12, 2019
概括
合成致死性利用了癌症治疗的遗传弱点. 研究人员发现WRN蛋白对于微卫星不稳定性 (MSI) 的癌细胞至关重要,使其成为潜在的药物点.
科学领域:
- 癌症学
- 遗传学
- 分子生物学
背景情况:
- 通过针对基因脆弱性, 合成致死性为癌症治疗提供了一个有前途的策略.
- 在癌症中,DNA修复途径的缺陷是常见的,导致对特定修复蛋白的依赖.
- 在同类重组缺陷癌症中,多种ADP- 核糖酶1 (PARP- 1) 抑制剂已经显示出成功.
研究的目的:
- 在微卫星不稳定性 (MSI) 的癌症中识别合成致命目标,这些癌症是由缺陷的DNA不匹配修复引起的.
- 研究MSI癌症对DNA修复蛋白的依赖性.
主要方法:
- 使用CRISPR-Cas9淘汰和RNA干扰的大规模沉默屏幕的分析.
- 在MSI和微卫星稳定的癌症模型中评估WRN (RecQ DNA helicase) 的依赖性.
- 在MSI癌症模型中评估WRN的酶和外核酶活动.
主要成果:
- 在MSI癌症模型中发现WRN具有选择性的必要性,但在微卫星稳定的模型中是不可用的.
- 在MSI模型中,WRN的耗尽导致了双链DNA断裂,细胞亡和细胞循环停止.
- MSI癌症模型需要WRN的酶活性,而不是它的外核酶活性.
结论:
- 在MSI癌症中, WRN代表了一种合成致命的漏洞.
- WRN是治疗MSI癌症的潜在药物标.
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