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J Radiat Res. 2019 Jan 1;60(1):37-50. doi: 10.1093/jrr/rry084.

Radiation resistance of normal human astrocytes: the role of non-homologous end joining DNA repair activity.

Author information

1
Department of Anatomy, Physiology, and Genetics, The Uniformed Services University of the Health Sciences, Jones Bridge Road, Bethesda, MD, USA.
2
Department of Pharmacology and Molecular Therapeutics, The Uniformed Services University of the Health Sciences, Jones Bridge Road, Bethesda, MD, USA.

Abstract

Radiotherapy is a common modality for treatment of brain cancers, but it can induce long-term physiological and cognitive deficits. The responses of normal human brain cells to radiation is not well understood. Astrocytes have been shown to have a variety of protective mechanisms against oxidative stress and have been shown to protect neurons. We investigated the response of cultured normal human astrocytes (NHAs) to X-ray irradiation. Following exposure to 10 Gy X-irradiation, NHAs exhibited DNA damage as indicated by the formation of γ-H2AX foci. Western blotting showed that NHAs displayed a robust increase in expression of non-homologous end joining DNA repair enzymes within 15 min post-irradiation and increased expression of homologous recombination DNA repair enzymes ~2 h post-irradiation. The cell cycle checkpoint protein p21/waf1 was upregulated from 6-24 h, and then returned to baseline. Levels of DNA repair enzymes returned to basal ~48 h post-irradiation. NHAs re-entered the cell cycle and proliferation was observed at 6 days. In contrast, normal human mesenchymal stem cells (MSCs) failed to upregulate DNA repair enzymes and instead displayed sustained upregulation of p21/waf1, a cell cycle checkpoint marker for senescence. Ectopic overexpression of Ku70 was sufficient to protect MSCs from sustained upregulation of p21/waf1 induced by 10 Gy X-rays. These findings suggest that increased expression of Ku70 may be a key mechanism for the radioresistance of NHAs, preventing their accelerated senescence from high-dose radiation. These results may have implications for the development of novel targets for radiation countermeasure development.

PMID:
30423138
PMCID:
PMC6373697
[Available on 2020-01-01]
DOI:
10.1093/jrr/rry084
[Indexed for MEDLINE]

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