DNA Repair as a Potential Mechanism for Proliferation of Normal Human Astrocytes after Ionizing Radiation Injury
Abstract
Radiation therapy is commonly used to treat brain malignancies, including primary tumors and metastases. However, due to damage of underlying normal brain tissues, this therapy is linked to long term cognitive impairments, changes in mood, memory and attention. Although neurons have been demonstrated to be sensitive to radiation injury, less research has been done to study normal human astrocytes and their response to radiation injury. Prior research into the ability of astrocytes to respond to various stressors indicates they are capable of utilizing multiple mechanisms to aid in their survival. Research has also demonstrated that astrocytes can provide protection to neurons in their environment. Based on previous studies, we hypothesized that normal human astrocytes would be capable of proliferating after radiation injury, potentially utilizing strong antioxidant responses and DNA repair mechanisms. We chose to compare the survival of normal astrocyte to mesenchymal stem cells (MSC), a well-studied normal human cell type considered to be relatively radiation resistant. We found that astrocytes proliferated after 10 Gy X-ray irradiation, but MSCs underwent accelerated senescence. Neither cell type displayed markers for necrotic cell death or apoptosis. We explored the mechanism of astrocyte radiation resistance. A thorough investigation of antioxidant enzyme responses demonstrated that astrocytes did not activate the redox response transcription factor Nrf2 or significantly upregulate Mn2+- superoxide dismutase, catalase, thioredoxin, or cellular glutathione levels. We next investigated DNA repair mechanisms in astrocytes. We found that nonhomologous end joining (NHEJ) and homologous recombination (HR) enzymes were increased in astrocytes in response to 10 Gy X-ray irradiation. Ku70, a critical NHEJ enzyme was upregulated ~6-fold within 15 min after irradiation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 05, 2018
- Accession Number
- AD1128187
Entities
People
- Michelle Bylicky
Organizations
- Uniformed Services University of the Health Sciences