Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands.
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Science, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Cells. 2022 Nov 27;11(23):3794. doi: 10.3390/cells11233794.
Cancer risk after ionizing radiation (IR) is assumed to be linear with the dose; however, for low doses, definite evidence is lacking. Here, using temporal multi-omic systems analyses after a low (LD; 0.1 Gy) or a high (HD; 1 Gy) dose of X-rays, we show that, although the DNA damage response (DDR) displayed dose proportionality, many other molecular and cellular responses did not. Phosphoproteomics uncovered a novel mode of phospho-signaling via S12-PPP1R7, and large-scale dephosphorylation events that regulate mitotic exit control in undamaged cells and the G2/M checkpoint upon IR in a dose-dependent manner. The phosphoproteomics of irradiated DNA double-strand breaks (DSBs) repair-deficient cells unveiled extended phospho-signaling duration in either a dose-dependent (DDR signaling) or independent (mTOR-ERK-MAPK signaling) manner without affecting signal magnitude. Nascent transcriptomics revealed the transcriptional activation of genes involved in NRF2-regulated antioxidant defense, redox-sensitive ERK-MAPK signaling, glycolysis and mitochondrial function after LD, suggesting a prominent role for reactive oxygen species (ROS) in molecular and cellular responses to LD exposure, whereas DDR genes were prominently activated after HD. However, how and to what extent the observed dose-dependent differences in molecular and cellular responses may impact cancer development remain unclear, as the induction of chromosomal damage was found to be dose-proportional (10-200 mGy).
人们认为，电离辐射（IR）后的癌症风险与剂量呈线性关系；然而，对于低剂量，目前还缺乏明确的证据。在这里，我们使用低剂量（LD；0.1Gy）或高剂量（HD；1Gy）X 射线照射后的时间多组学系统分析，表明虽然 DNA 损伤反应（DDR）显示出剂量比例性，但许多其他分子和细胞反应并没有。磷酸蛋白质组学揭示了一种通过 S12-PPP1R7 进行磷酸信号传递的新方式，以及大规模的去磷酸化事件，这些事件以剂量依赖的方式调节未受损细胞的有丝分裂退出控制和 IR 后的 G2/M 检查点。受照射 DNA 双链断裂（DSB）修复缺陷细胞的磷酸蛋白质组学揭示了延长的磷酸信号传递持续时间，无论是剂量依赖性（DDR 信号）还是独立的（mTOR-ERK-MAPK 信号），而不影响信号幅度。新生转录组学揭示了 LD 后涉及 NRF2 调节的抗氧化防御、氧化还原敏感的 ERK-MAPK 信号、糖酵解和线粒体功能的基因的转录激活，表明活性氧（ROS）在 LD 暴露后的分子和细胞反应中起着重要作用，而 DDR 基因在 HD 后被明显激活。然而，观察到的分子和细胞反应中的剂量依赖性差异如何以及在何种程度上可能影响癌症的发展尚不清楚，因为染色体损伤的诱导被发现与剂量成比例（10-200mGy）。
