Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.
Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.
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DOI：
10.1126/science.1257216
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发表时间：
2015-01-16
期刊：
影响因子：
--
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Flynn RL;Cox KE;Jeitany M;Wakimoto H;Bryll AR;Ganem NJ;Bersani F;Pineda JR;Suvà ML;Benes CH;Haber DA;Boussin FD;Zou L
癌细胞依靠端粒酶或替代端粒延长（ALT）途径来克服复制性死亡。ALT是由重组介导的，在人类癌症的一个子集中普遍存在，但它是否可以用于治疗仍然未知。癌症中染色质重塑蛋白ATRX的缺失与ALT相关。在这里，我们发现ATRX的缺失损害了端粒非编码RNA TERRA的细胞周期调节，并导致DNA复制后复制蛋白A （RPA）与端粒的持续结合，从而产生重组核蛋白结构。蛋白激酶ATR是RPA募集的重组的关键调节因子，抑制ATR可破坏ALT并引发ALT细胞的染色体断裂和凋亡。重要的是，ATR抑制剂诱导的细胞死亡对依赖ALT的癌细胞具有高度选择性，这表明此类抑制剂可能对ALT阳性癌症的治疗有用。
Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric non-coding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. Importantly, the cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, , suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.
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