PARP inhibitors have emerged as effective chemotherapeutic agents for BRCA1/BRCA2-deficient cancers. Another DNA damage response protein, ATM, is also increasingly being recognized as a target for synthetic lethality with PARP inhibitors. As ATM functions in both cell cycle arrest and DNA repair after DNA damage, how cells respond to inhibition of ATM and PARP1 is yet to be defined precisely. We found that loss of ATM function, either in an ATM-deficient background or after treatment with ATM inhibitors (KU-60019 or AZD0156), results in spontaneous DNA damage and an increase in PARylation. When PARP1 is also deleted or inhibited with inhibitors (olaparib or veliparib), the massive increase in DNA damage activates the G2 DNA damage checkpoint kinase cascade involving ATR, CHK1/2, and WEE1. Our data indicated that the role of ATM in DNA repair is critical for the synergism with PARP inhibitors. Bypass of the G2 DNA damage checkpoint in the absence of ATM functions occurs only after a delay. The relative insensitivity of PARP1-deficient cells to PARP inhibitors suggested that other PARP isoforms played a relatively minor role in comparison with PARP1 in synergism with ATMi. As deletion of PARP1 also increased sensitivity to ATM inhibitors, trapping of PARP1 on DNA may not be the only mechanism involved in the synergism between PARP1 and ATM inhibition. Collectively, these studies provide a mechanistic foundation for therapies targeting ATM and PARP1.

中文翻译：

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ATM和PARP1抑制作用之间的协同作用涉及DNA损伤并放弃G2 DNA损伤检查点。

PARP抑制剂已成为BRCA1 / BRCA2缺陷型癌症的有效化疗药物。另一种DNA损伤反应蛋白ATM也日益被人们认为是使用PARP抑制剂合成致死性的靶标。由于ATM在DNA损伤后在细胞周期停滞和DNA修复中均起作用，因此细胞对ATM和PARP1抑制的反应尚不清楚。我们发现，在ATM缺乏的背景下或用ATM抑制剂（KU-60019或AZD0156）处理后，ATM功能的丧失都会导致DNA的自发损伤和PARylation的增加。当PARP1也被抑制剂（奥拉帕尼或veliparib）删除或抑制时，DNA损伤的大量增加激活了涉及ATR，CHK1 / 2和WEE1的G2 DNA损伤检查点激酶级联反应。我们的数据表明，ATM在DNA修复中的作用对于与PARP抑制剂的协同作用至关重要。在没有ATM功能的情况下，绕过G2 DNA损坏检查点的操作仅在延迟之后才会发生。缺乏PARP1的细胞对PARP抑制剂的相对不敏感性表明，与PARP1在与ATMi协同作用中相比，其他PARP同工型发挥的作用相对较小。由于PARP1的缺失也增加了对ATM抑制剂的敏感性，因此将PARP1捕获在DNA上可能不是参与PARP1和ATM抑制作用协同作用的唯一机制。这些研究共同为针对ATM和PARP1的疗法提供了机制基础。缺乏PARP1的细胞对PARP抑制剂的相对不敏感性表明，与PARP1在与ATMi协同作用中相比，其他PARP同工型发挥的作用相对较小。由于PARP1的缺失也增加了对ATM抑制剂的敏感性，因此将PARP1捕获在DNA上可能不是参与PARP1和ATM抑制作用协同作用的唯一机制。这些研究共同为针对ATM和PARP1的疗法提供了机制基础。缺乏PARP1的细胞对PARP抑制剂的相对不敏感性表明，与PARP1在与ATMi协同作用中相比，其他PARP同工型发挥的作用相对较小。由于PARP1的缺失也增加了对ATM抑制剂的敏感性，因此将PARP1捕获在DNA上可能不是参与PARP1和ATM抑制作用协同作用的唯一机制。这些研究共同为针对ATM和PARP1的疗法提供了机械基础。