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Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents

机译：ATR的消耗选择性地使ATM缺陷型人类乳腺上皮细胞对电离辐射和DNA破坏剂敏感

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摘要

DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). ATM and ATR are central players in activating cell cycle checkpoints and function as an active barrier against genome instability and tumorigenesis in replicating cells. Loss of ATM function is frequently reported in various types of tumors, thus placing more reliance on ATR for checkpoint arrest and cell survival following DNA damage. To investigate the role of ATR in the G2/M checkpoint regulation in response to ionizing radiation (IR), particularly when ATM is deficient, cell lines deficient of ATM, ATR, or both were generated using a doxycycline-inducible lentiviral system. Our data suggests that while depletion of ATR or ATM alone in wild-type human mammary epithelial cell cultures (HME-CCs) has little effect on radiosensitivity or IR-induced G2/M checkpoint arrest, depletion of ATR in ATM-deficient cells causes synthetic lethality following IR, which correlates with severe G2/M checkpoint attenuation. ATR depletion also inhibits IR-induced autophagy, regardless of the ATM status, and enhances IR-induced apoptosis particularly when ATM is deficient. Collectively, our results clearly demonstrate that ATR function is required for the IR-induced G2/M checkpoint activation and subsequent survival of cells with ATM deficiency. The synthetic lethal interaction between ATM and ATR in response to IR supports ATR as a therapeutic target for improved anti-cancer regimens, especially in tumors with a dysfunctional ATM pathway.
机译：对双链断裂的DNA损伤反应（DDR）由3个磷脂酰肌醇3-激酶相关激酶（PIKK）家族成员协调：共济失调-毛细血管扩张突变激酶（ATM），ATM和Rad3相关（ATR）激酶以及催化DNA依赖性蛋白激酶（DNA-PKcs）的亚基。 ATM和ATR是激活细胞周期检查点的主要角色，并充当复制细胞中基因组不稳定和肿瘤发生的主动屏障。在各种类型的肿瘤中经常报告ATM功能丧失，因此在DNA损伤后检查点停滞和细胞存活更加依赖ATR。为了研究ATR在响应电离辐射（IR）时在G2 / M检查点调节中的作用，特别是当ATM不足时，使用强力霉素诱导的慢病毒系统生成了ATM和/或ATR不足的细胞系。我们的数据表明，虽然在野生型人乳腺上皮细胞培养物（HME-CC）中仅消耗ATR或ATM对放射敏感性或IR诱导的G2 / M检查点停滞几乎没有影响，但在ATM不足的细胞中消耗ATR会导致合成IR致死率，这与严重的G2 / M检查点衰减相关。无论ATM处于何种状态，ATR耗竭也会抑制IR诱导的自噬，并增强IR诱导的凋亡，特别是当ATM不足时。总的来说，我们的结果清楚地表明，IR诱导的G2 / M检查点激活以及具有ATM缺陷的细胞的随后存活需要ATR功能。 ATM和ATR之间对IR的合成致死性相互作用支持ATR作为改善抗癌方案的治疗靶标，特别是在ATM通路功能异常的肿瘤中。

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