Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation
Bharath Sampadi,
Sylvia Vermeulen,
Branislav Mišovic,
Jan J. Boei,
Tanveer S. Batth,
Jer-Gung Chang,
Michelle T. Paulsen,
Brian Magnuson,
Joost Schimmel,
Hanneke Kool,
Cyriel S. Olie,
Bart Everts,
Alfred C. O. Vertegaal,
Jesper V. Olsen,
Mats Ljungman,
Penny A. Jeggo,
Leon H. F. Mullenders,
Harry Vrieling
Affiliations
Bharath Sampadi
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Sylvia Vermeulen
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Branislav Mišovic
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Jan J. Boei
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Tanveer S. Batth
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Science, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
Jer-Gung Chang
Department of Cell and Chemical Biology, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Michelle T. Paulsen
Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI 48109, USA
Brian Magnuson
Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI 48109, USA
Joost Schimmel
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Hanneke Kool
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Cyriel S. Olie
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Bart Everts
Department of Parasitology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands
Alfred C. O. Vertegaal
Department of Cell and Chemical Biology, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Jesper V. Olsen
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Science, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
Mats Ljungman
Department of Radiation Oncology, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI 48109, USA
Penny A. Jeggo
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK
Leon H. F. Mullenders
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
Harry Vrieling
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, The Netherlands
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).
