Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation

被引:10
|
作者
Sampadi, Bharath [1 ]
Vermeulen, Sylvia [1 ]
Misovic, Branislav [1 ]
Boei, Jan J. J. [1 ]
Batth, Tanveer S. S. [2 ]
Chang, Jer-Gung [3 ]
Paulsen, Michelle T. T. [4 ,5 ]
Magnuson, Brian [4 ,5 ]
Schimmel, Joost [1 ]
Kool, Hanneke [1 ]
Olie, Cyriel S. S. [1 ]
Everts, Bart [6 ]
Vertegaal, Alfred C. O. [3 ]
Olsen, Jesper V. V. [2 ]
Ljungman, Mats [4 ,5 ]
Jeggo, Penny A. A. [7 ]
Mullenders, Leon H. F. [1 ,8 ]
Vrieling, Harry [1 ]
机构
[1] Leiden Univ Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands
[2] Univ Copenhagen, Novo Nord Fdn Ctr Prot Res, Fac Hlth & Med Sci, Prote Program, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark
[3] Leiden Univ Med Ctr, Dept Cell & Chem Biol, NL-2333 ZC Leiden, Netherlands
[4] Univ Michigan, Rogel Canc Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
[5] Univ Michigan, Ctr RNA Biomed, Ann Arbor, MI 48109 USA
[6] Leiden Univ Med Ctr, Dept Parasitol, NL-2333 ZA Leiden, Netherlands
[7] Univ Sussex, Genome Damage & Stabil Ctr, Sch Life Sci, Brighton BN1 9RQ, England
[8] Nagoya Univ, Res Inst Environm Med RIeM, Dept Genet, Nagoya 4648601, Japan
关键词
ionizing radiation; low dose; linear no-threshold; signal transduction; cell signaling; DNA damage response; phosphoproteomics; mitochondria; reactive oxygen species; antioxidant response; DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; OXIDATIVE STRESS; MITOTIC EXIT; QUANTITATIVE PHOSPHOPROTEOMICS; STEM-CELLS; PHOSPHORYLATION; PROTEIN; ATM; DYNAMICS;
D O I
10.3390/cells11233794
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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).
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页数:25
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