High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity

Abstract

Cranial irradiation is part of the standard of care for treating pediatric brain tumors. However, ionizing radiation can trigger serious long-term neurologic sequelae, including oligodendrocyte and brain white matter loss enabling neurocognitive decline in children surviving brain cancer. Oxidative stress-mediated oligodendrocyte precursor cell (OPC) radiosensitivity has been proposed as a possible explanation for this. Here, however, we demonstrate that antioxidants fail to improve OPC viability after irradiation, despite suppressing oxidative stress, suggesting an alternative etiology for OPC radiosensitivity. Using systematic approaches, we find that OPCs have higher irradiation-induced and endogenous γH2AX foci compared to neural stem cells, neurons, astrocytes and mature oligodendrocytes, and these correlate with replication-associated DNA double strand breakage. Furthermore, OPCs are reliant upon ATR kinase and Mre11 nuclease-dependent processes for viability, are more sensitive to drugs increasing replication fork collapse, and display synthetic lethality with PARP inhibitors after irradiation. This suggests an insufficiency for homology-mediated DNA repair in OPCs—a model that is supported by evidence of normal RPA but reduced RAD51 filament formation at resected lesions in irradiated OPCs. We therefore propose a DNA repair-centric mechanism of OPC radiosensitivity, involving chronically-elevated replication stress combined with ‘bottlenecks’ in RAD51-dependent DNA repair that together reduce radiation resilience.

Delayed Maturation of Oligodendrocyte Progenitors by Microgravity: Implications for Multiple Sclerosis and Space Flight

“…Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/) exposures of mice to a mixed field of neutrons and photons resulted in diminished hippocampal neuronal excitability and disrupted long-term potentiation with severe impairments in learning, memory, and concomitant distress behaviors [ 52 ]. In the case of OLPs in an in vitro model of OLPs exposed to protons/HZE radiation, alterations in DNA repair protein Apurinic Endonuclease-1(APE1) expression in the nuclei and mitochondria have been described [ 53 ]. Moreover, ionizing radiation (IR) that is used to treat central nervous system (CNS) tumors has been reported to cause impaired OLPs’ differentiation and maturation as well as a decreased number of mature OLs, leading to white matter loss and impaired cognition [ 54 ].…”