Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G2-phase
Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G2-phase
复制标题
DOI：
10.1038/s41598-019-44771-6
复制
发表时间：
2019-06-04
影响因子：
4.6
通讯作者：
Iliakis, George
中科院分区：
文献类型：
--
作者：
Mladenov, Emil;Fan, Xiaoxiang;Iliakis, George
使用与细胞暴露于电离辐射（IR）在G2期的细胞周期中产生的数据，我们描述了ATM，ATR和DNA-PKcs之间的剂量依赖性相互作用，揭示了DNA损伤反应的两个关键方面未知的机制基础：DSB末端切除和G2检查点激活。在诱导基因组中低DSB数目的低IR剂量下，ATM和ATR上位性地调节G2检查点，ATR在输出节点处，主要通过Chk 1与细胞周期介导。引人注目的是，在低IR剂量下，ATM和ATR也上位调节切除，并且抑制任一活性完全抑制切除。在诱导基因组中的高DSB数目的高IR剂量下，紧密的ATM/ATR偶联松弛并且发生到G2检查点和切除的独立输出。因此，必须抑制这两种激酶以完全抑制检查点激活和切除。DNA-PKcs通过在所有IR剂量下调节切除而整合到ATM/ATR模块，DNA-PKcs中的缺陷引起超切除和G2检查点超激活。值得注意的是，其他c-NHEJ突变体不存在过度切除。因此，DNA-PKcs特异性地调节切除并调节ATM/ATR模块的激活。我们建议，选定的DSB是牧羊人的DNA-PKcs从c-NHEJ切除依赖的途径下的ATM/ATR模块的监管监督处理。
Using data generated with cells exposed to ionizing-radiation (IR) in G2-phase of the cell cycle, we describe dose-dependent interactions between ATM, ATR and DNA-PKcs revealing unknown mechanistic underpinnings for two key facets of the DNA damage response: DSB end-resection and G2-checkpoint activation. At low IR-doses that induce low DSB-numbers in the genome, ATM and ATR regulate epistatically the G2-checkpoint, with ATR at the output-node, interfacing with the cell-cycle predominantly through Chk1. Strikingly, at low IR-doses, ATM and ATR epistatically regulate also resection, and inhibition of either activity fully suppresses resection. At high IR-doses that induce high DSB-numbers in the genome, the tight ATM/ATR coupling relaxes and independent outputs to G2-checkpoint and resection occur. Consequently, both kinases must be inhibited to fully suppress checkpoint activation and resection. DNA-PKcs integrates to the ATM/ATR module by regulating resection at all IR-doses, with defects in DNA-PKcs causing hyper-resection and G2-checkpoint hyperactivation. Notably, hyper-resection is absent from other c-NHEJ mutants. Thus, DNA-PKcs specifically regulates resection and adjusts the activation of the ATM/ATR module. We propose that selected DSBs are shepherd by DNA-PKcs from c-NHEJ to resection-dependent pathways for processing under the regulatory supervision of the ATM/ATR module.