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WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Nature ( IF 50.5 ) Pub Date : 2019-04-01 , DOI: 10.1038/s41586-019-1102-x
Edmond M Chan 1, 2 , Tsukasa Shibue 1 , James M McFarland 1 , Benjamin Gaeta 1 , Mahmoud Ghandi 1 , Nancy Dumont 1 , Alfredo Gonzalez 1 , Justine S McPartlan 1 , Tianxia Li 2 , Yanxi Zhang 2 , Jie Bin Liu 2 , Jean-Bernard Lazaro 3 , Peili Gu 4 , Cortt G Piett 5 , Annie Apffel 1 , Syed O Ali 1, 2 , Rebecca Deasy 1 , Paula Keskula 1 , Raymond W S Ng 1, 2 , Emma A Roberts 3 , Elizaveta Reznichenko 3 , Lisa Leung 1 , Maria Alimova 1 , Monica Schenone 1 , Mirazul Islam 1, 2 , Yosef E Maruvka 1, 6 , Yang Liu 1, 2 , Jatin Roper 7 , Srivatsan Raghavan 1, 2 , Marios Giannakis 1, 2 , Yuen-Yi Tseng 1 , Zachary D Nagel 1, 5 , Alan D'Andrea 3 , David E Root 1 , Jesse S Boehm 1 , Gad Getz 1, 6 , Sandy Chang 4, 8, 9 , Todd R Golub 1, 10, 11 , Aviad Tsherniak 1 , Francisca Vazquez 1, 2 , Adam J Bass 1, 2
Nature ( IF 50.5 ) Pub Date : 2019-04-01 , DOI: 10.1038/s41586-019-1102-x
Edmond M Chan 1, 2 , Tsukasa Shibue 1 , James M McFarland 1 , Benjamin Gaeta 1 , Mahmoud Ghandi 1 , Nancy Dumont 1 , Alfredo Gonzalez 1 , Justine S McPartlan 1 , Tianxia Li 2 , Yanxi Zhang 2 , Jie Bin Liu 2 , Jean-Bernard Lazaro 3 , Peili Gu 4 , Cortt G Piett 5 , Annie Apffel 1 , Syed O Ali 1, 2 , Rebecca Deasy 1 , Paula Keskula 1 , Raymond W S Ng 1, 2 , Emma A Roberts 3 , Elizaveta Reznichenko 3 , Lisa Leung 1 , Maria Alimova 1 , Monica Schenone 1 , Mirazul Islam 1, 2 , Yosef E Maruvka 1, 6 , Yang Liu 1, 2 , Jatin Roper 7 , Srivatsan Raghavan 1, 2 , Marios Giannakis 1, 2 , Yuen-Yi Tseng 1 , Zachary D Nagel 1, 5 , Alan D'Andrea 3 , David E Root 1 , Jesse S Boehm 1 , Gad Getz 1, 6 , Sandy Chang 4, 8, 9 , Todd R Golub 1, 10, 11 , Aviad Tsherniak 1 , Francisca Vazquez 1, 2 , Adam J Bass 1, 2
Affiliation
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Synthetic lethality—an interaction between two genetic events through which the co-occurrence of these two genetic events leads to cell death, but each event alone does not—can be exploited for cancer therapeutics1. DNA repair processes represent attractive synthetic lethal targets, because many cancers exhibit an impairment of a DNA repair pathway, which can lead to dependence on specific repair proteins2. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach3. Hypothesizing that other DNA repair defects would give rise to synthetic lethal relationships, we queried dependencies in cancers with microsatellite instability (MSI), which results from deficient DNA mismatch repair. Here we analysed data from large-scale silencing screens using CRISPR–Cas9-mediated knockout and RNA interference, and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, yet dispensable in models of cancers that are microsatellite stable. Depletion of WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models required the helicase activity of WRN, but not its exonuclease activity. These findings show that WRN is a synthetic lethal vulnerability and promising drug target for MSI cancers.Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
中文翻译:
WRN解旋酶是微卫星不稳定癌症的合成致死靶标
合成致死性是两个遗传事件之间的相互作用,通过该相互作用,这两个遗传事件的同时发生会导致细胞死亡,但每个事件单独不会导致细胞死亡,可用于癌症治疗1。 DNA 修复过程代表了有吸引力的合成致死靶点,因为许多癌症表现出 DNA 修复途径受损,这可能导致对特定修复蛋白的依赖2。聚(ADP-核糖)聚合酶 1 (PARP-1) 抑制剂在同源重组缺陷的癌症中取得的成功凸显了这种方法的潜力3。假设其他 DNA 修复缺陷会导致合成致死关系,我们询问了癌症与微卫星不稳定性 (MSI) 的依赖性,微卫星不稳定性 (MSI) 是由 DNA 错配修复缺陷引起的。在这里,我们使用 CRISPR-Cas9 介导的敲除和 RNA 干扰分析了大规模沉默筛选的数据,发现 RecQ DNA 解旋酶 WRN 在体外和体内 MSI 模型中选择性必需,但在微卫星癌症模型中是可有可无的稳定的。在 MSI 模型中,WRN 的消耗会诱导双链 DNA 断裂,并选择性地促进细胞凋亡和细胞周期停滞。 MSI 癌症模型需要 WRN 的解旋酶活性,但不需要其核酸外切酶活性。这些发现表明,WRN 是 MSI 癌症的合成致命弱点和有希望的药物靶点。 DNA 解旋酶 WRN 的耗尽会诱导双链 DNA 断裂,并在具有微卫星不稳定性的癌症中选择性地促进细胞凋亡和细胞周期停滞,表明 WRN 是一种治疗这些癌症的有希望的药物靶点。
更新日期:2019-04-01
中文翻译:
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WRN解旋酶是微卫星不稳定癌症的合成致死靶标
合成致死性是两个遗传事件之间的相互作用,通过该相互作用,这两个遗传事件的同时发生会导致细胞死亡,但每个事件单独不会导致细胞死亡,可用于癌症治疗1。 DNA 修复过程代表了有吸引力的合成致死靶点,因为许多癌症表现出 DNA 修复途径受损,这可能导致对特定修复蛋白的依赖2。聚(ADP-核糖)聚合酶 1 (PARP-1) 抑制剂在同源重组缺陷的癌症中取得的成功凸显了这种方法的潜力3。假设其他 DNA 修复缺陷会导致合成致死关系,我们询问了癌症与微卫星不稳定性 (MSI) 的依赖性,微卫星不稳定性 (MSI) 是由 DNA 错配修复缺陷引起的。在这里,我们使用 CRISPR-Cas9 介导的敲除和 RNA 干扰分析了大规模沉默筛选的数据,发现 RecQ DNA 解旋酶 WRN 在体外和体内 MSI 模型中选择性必需,但在微卫星癌症模型中是可有可无的稳定的。在 MSI 模型中,WRN 的消耗会诱导双链 DNA 断裂,并选择性地促进细胞凋亡和细胞周期停滞。 MSI 癌症模型需要 WRN 的解旋酶活性,但不需要其核酸外切酶活性。这些发现表明,WRN 是 MSI 癌症的合成致命弱点和有希望的药物靶点。 DNA 解旋酶 WRN 的耗尽会诱导双链 DNA 断裂,并在具有微卫星不稳定性的癌症中选择性地促进细胞凋亡和细胞周期停滞,表明 WRN 是一种治疗这些癌症的有希望的药物靶点。