Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase.
Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase.
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DOI：
10.1016/j.molcel.2015.07.029
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发表时间：
2015-09-17
期刊：
影响因子：
16
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
ATR-Chk 1通路对DNA损伤反应和细胞周期进程至关重要。Chk 1抑制比ATR抑制对循环细胞更有害，在没有外部复制应激的情况下提出了ATR和Chk 1功能的问题。在这里，我们表明，ATR在S期的一个关键作用是协调RRM 2积累和起源放电。ATR抑制剂（ATRi）在一部分早期S期细胞中诱导大量ssDNA积累和复制灾难。然而，在其他S期细胞中，ATRi诱导中度ssDNA并触发DNA-PK和Chk 1介导的备用途径以抑制起源放电。备用途径产生阈值，使得ATRi在高复制应激下选择性地杀死细胞，而Chk 1抑制剂在较低阈值下诱导细胞死亡。ATRi诱导的ssDNA的水平与一组细胞系中的ATRi敏感性相关，表明ATRi诱导的ssDNA可以预测癌细胞中的ATRi敏感性。
The ATR-Chk1 pathway is critical for DNA damage responses and cell cycle progression. Chk1 inhibition is more deleterious to cycling cells than ATR inhibition, raising questions about ATR and Chk1 functions in the absence of extrinsic replication stress. Here, we show that a key role of ATR in S phase is to coordinate RRM2 accumulation and origin firing. ATR inhibitor (ATRi) induces massive ssDNA accumulation and replication catastrophe in a fraction of early S-phase cells. In other S-phase cells, however, ATRi induces moderate ssDNA and triggers a DNA-PK and Chk1-mediated backup pathway to suppress origin firing. The backup pathway creates a threshold such that ATRi selectively kills cells under high replication stress, whereas Chk1 inhibitor induces cell death at a lower threshold. The levels of ATRi-induced ssDNA correlate with ATRi sensitivity in a panel of cell lines, suggesting that ATRi-induced ssDNA could be predictive of ATRi sensitivity in cancer cells.