Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection.
Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection.
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ATM 和 Fanconi 贫血/BRCA 途径在双链断裂末端切除中的合作
DOI：
10.1016/j.celrep.2020.01.052
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发表时间：
2020-02-18
期刊：
影响因子：
8.8
通讯作者：
D'Andrea AD
中科院分区：
文献类型：
--
作者：
Cai MY;Dunn CE;Chen W;Kochupurakkal BS;Nguyen H;Moreau LA;Shapiro GI;Parmar K;Kozono D;D'Andrea AD
缺乏共济失调毛细血管扩张突变 (ATM) 的细胞对电离辐射和其他诱导双链 DNA 断裂的抗癌药物过敏。因此，ATM 抑制剂可能会使癌细胞对这些药物敏感。一些癌症也可能具有潜在的遗传缺陷，使其容易对 ATM 抑制剂单一疗法产生反应。我们进行了全基因组 CRISPR 筛选，以确定使肺癌细胞对 ATM 抑制剂敏感的遗传漏洞。范可尼贫血 (FA)/BRCA 通路中的基因敲除会导致对 ATM 抑制剂 M3541 过敏。敲低 FA 基因或 ATM 会导致双链断裂末端切除减少、非同源末端连接 (NHEJ) 修复增强、同源重组修复减少。 FA/BRCA 途径和 ATM 的敲除会强烈抑制末端切除并产生有毒水平的 NHEJ，从而阐明合成致死引起的细胞死亡机制。因此，ATM 抑制剂可能可用于治疗 FA/BRCA 通路缺陷的肿瘤。 ATM 抑制剂目前正作为抗癌药物进行临床开发。 Cai 等人使用全基因组 CRISPR 筛选。证明具有范可尼贫血 (FA) 途径缺陷的癌细胞对 ATM 抑制敏感。作者还表明，ATM 和 FA 途径之间的合成致死率是由于 DNA 切除减少和毒性 NHEJ 增加所致。
Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-wide CRISPR screen to identify genetic vulnerabilities that sensitize lung cancer cells to ATM inhibitors. Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541. Knockdown of either an FA gene or of ATM results in reduced double-strand break end resection, enhanced non-homologous end joining (NHEJ) repair, and decreased homologous recombination repair. Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway. ATM inhibitors are currently in clinical development as anti-cancer agents. Using a genome-wide CRISPR screen, Cai et al. demonstrate that cancer cells with Fanconi anemia (FA) pathway deficiency are sensitive to ATM inhibition. The authors also show that synthetic lethality between ATM and the FA pathway is due to reduced DNA resection and increased toxic NHEJ.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
DOI：
10.18632/aging.100334
发表时间：
2011-05
期刊：
Aging
影响因子：
--
作者：
Harris JL;Khanna KK
通讯作者：
Khanna KK
影响因子：
5.7
作者：
Batey MA;Zhao Y;Kyle S;Richardson C;Slade A;Martin NM;Lau A;Newell DR;Curtin NJ
通讯作者：
Curtin NJ
影响因子：
64.8
作者：
Mateos-Gomez PA;Gong F;Nair N;Miller KM;Lazzerini-Denchi E;Sfeir A
通讯作者：
Sfeir A
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE