Translationally Controlled Tumor Protein Induced by Low-Dose Radiation Protects Against DNA Damage
In research published online in the Proceedings of the National Academies of Science, scientists at the University of Medicine and Dentistry of New Jersey and the Fourth Military Medical University in the People's Republic of China described an important role of a multifunctional protein in response to low dose radiation-induced DNA damage. The translationally controlled tumor protein (TCTP) is highly conserved and is found in mammals, plants, and yeast. It is a jack of all trades that participates in numerous cellular processes, including protein synthesis, cell growth and allergic reactions. Mice that lack both copies of the TCTP gene die in utero. The recent work has uncovered a critical role of TCTP in a cell's ability to repair DNA damage and maintain genomic integrity in response to stressful agents.
When they exposed normal human cells to low doses of cesium-137 gamma rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on the early sensors of DNA damage, specifically the ataxia-telangiectasia mutated (ATM) protein and the enzyme DNA-dependent protein kinase (DNA-PK). Importantly, this up-regulation was associated with protective effects against DNA damage.
The researchers previously observed important adaptive responses when normal human cells were exposed to low doses of cesium-137 gamma rays that mimic human exposure during diagnostic radiography or occupational activities. Specifically, these irradiated cells exhibited significantly less chromosomal damage than what occurred spontaneously in the corresponding non-irradiated cells. Their recent findings show that these protective effects do not occur in the absence of TCTP. Cells that lacked TCTP failed to repair their damaged DNA. In the chromatin of irradiated cells, TCTP physically interacts with ATM and exists in a complex with γH2A.X, a protein that marks the sites of DNA damage.
Translationally controlled tumor protein is a multifunctional protein that is highly conserved and abundantly expressed in eukaryotes. It has no sequence similar to other known proteins. In general, TCTP is thought to promote cell viability through an anti-apoptotic role. However, its role in other prosurvival mechanisms is unclear.
This finding is in agreement with its distinct localization with the foci of the DNA damage marker proteins γH2A.X, 53BP1 and P-ATM. Further, TCTP interacts with the DNA-binding subunits Ku70 and Ku80 of DNA-PK, a protein with a major role in repair of DNA double strand breaks, a particularly harmful form of DNA damage. These findings are consistent with the observation that TCTP is needed for Ku70 and Ku80 to reach their destination in the nuclei of cells harboring DNA damage.
TCTP is upregulated in the cytoplasm and nuclei of irradiated normal human cells, particularly following exposure to low doses of gamma rays. It is regulated in an ATM- and DNA-PK-dependent manner. In the nuclei of irradiated cells, it exists in complex within critical mediators of the DNA damage response; it colocalizes with P-ATM, 53BP1, and γH2A.X foci, which are DNA damage-associated sites. Its knockdown attenuates the DNA-binding activity of Ku70 and Ku80 and prevents normal repair of radiation-induced DNA damage. This knockdown also modulates the G1
cell cycle checkpoints. (IR, irradiation; NHEJ, nonhomologous end-joining; HR homologous recombination)
Why it matters: Ionizing radiation is used commonly in medical diagnostics, and there is concern about the potential damage and risk induced. These studies were focused on investigating molecular events involved in the sensing and repair of DNA damage following radiation exposure. A major focus of radiation biologists is to understand the cellular responses to low doses of radiation that mimic human exposure during diagnostic radiography or occupational activities and to relate these to risk from exposures. This study demonstrates that after exposure to low doses of ionizing radiation, mechanisms are activated that have the potential to stimulate protective mechanisms that could reduce the risk.
Acknowledgments: The work was supported by the U.S. Department of Energy Low Dose Radiation Research Program, the National Aeronautics Space Administration, the National Institutes of Health, and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), Ministry of Education of China.
Reference: J Zhang, BN Pandev, G Guo, D Pain, H Li, and EI Azzam. 2012. "Role of the translationally controlled tumor protein in DNA damage sensing and repair." Proceedings of the National Academy of Sciences 109(16):E926-E933.