Genetic vulnerabilities upon inhibition of DNA damage response.
Genetic vulnerabilities upon inhibition of DNA damage response.
复制标题
抑制DNA损伤反应后的遗传脆弱性。
DOI：
10.1093/nar/gkab643
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发表时间：
2021-08-20
影响因子：
14.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Wang C;Tang M;Chen Z;Nie L;Li S;Xiong Y;Szymonowicz KA;Park JM;Zhang H;Feng X;Huang M;Su D;Hart T;Chen J
由于DNA损伤反应（DDR）在维持基因组完整性、细胞稳态和肿瘤抑制中的重要作用，靶向DDR已成为癌症治疗的有希望的治疗策略。然而，靶向DDR的癌症治疗的益处是有限的，主要是由于缺乏预测性生物标志物。为了应对这一挑战，我们进行了CRISPR筛选，以寻找影响细胞对DDR抑制反应的遗传漏洞。通过使用靶向关键DDR介体（即ATR、ATM、DNAPK和CHK 1）的抑制剂进行CRISPR筛选，我们获得了与DDR抑制的遗传相互作用的全局和无偏见的观点。具体而言，我们确定YWHAE损失作为对CHK1抑制敏感性的关键决定因素。我们发现，KLHL15的损失保护细胞免受ATM抑制诱导的DNA损伤。此外，我们验证了APEX 1缺失使细胞对DNAPK抑制敏感。此外，我们比较了组合不同DDR抑制剂的协同效应，发现ATM抑制剂加PARP抑制剂诱导了显著水平的细胞死亡，可能是通过促进细胞凋亡。我们的研究结果增强了对DDR途径的理解，并将促进DDR靶向药物在癌症治疗中的应用。
Because of essential roles of DNA damage response (DDR) in the maintenance of genomic integrity, cellular homeostasis, and tumor suppression, targeting DDR has become a promising therapeutic strategy for cancer treatment. However, the benefits of cancer therapy targeting DDR are limited mainly due to the lack of predictive biomarkers. To address this challenge, we performed CRISPR screens to search for genetic vulnerabilities that affect cells’ response to DDR inhibition. By undertaking CRISPR screens with inhibitors targeting key DDR mediators, i.e. ATR, ATM, DNAPK and CHK1, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Specifically, we identified YWHAE loss as a key determinant of sensitivity to CHK1 inhibition. We showed that KLHL15 loss protects cells from DNA damage induced by ATM inhibition. Moreover, we validated that APEX1 loss sensitizes cells to DNAPK inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results enhance the understanding of DDR pathways and will facilitate the use of DDR-targeting agents in cancer therapy.
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DOI：
10.1083/jcb.201204035
发表时间：
2012-08-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Daniel JA;Pellegrini M;Lee BS;Guo Z;Filsuf D;Belkina NV;You Z;Paull TT;Sleckman BP;Feigenbaum L;Nussenzweig A
通讯作者：
Nussenzweig A
ATM 和 Fanconi 贫血/BRCA 途径在双链断裂末端切除中的合作
影响因子：
8.8
作者：
Cai MY;Dunn CE;Chen W;Kochupurakkal BS;Nguyen H;Moreau LA;Shapiro GI;Parmar K;Kozono D;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
16.6
作者：
Ferretti, Lorenza P.;Himmels, Sarah-Felicitas;Trenner, Anika;Walker, Christina;von Aesch, Christine;Eggenschwiler, Aline;Murina, Olga;Enchev, Radoslav I.;Peter, Matthias;Freire, Raimundo;Porro, Antonio;Sartori, Alessandro A.
通讯作者：
Sartori, Alessandro A.
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
4.3
作者：
Hurley, Paula J.;Bunz, Fred
通讯作者：
Bunz, Fred