Chan, Jennifer A. W.Goodarzi, Aaron A.Berger, Nelson Daniel2020-05-142020-05-142020-05-12Berger, N. D. (2020). Investigating radiosensitivity and DNA repair in different neural cell types (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/112050Cranial radiotherapy (CRT) is an important and effective treatment for childhood brain cancers, but is also strongly associated with persistent neurocognitive decline, a heightened risk of secondary radiation-induced malignancies and altered white matter developmental trajectory. These late effects of CRT increase in severity the younger a patient is treated. Despite substantial advances in radiotherapy planning and treatment, late effects remain an issue to the ever-increasing group of childhood cancer survivors. The cellular and molecular mechanisms of these late effects are largely unknown, and the subtleties of how a developing, pediatric brain interacts with the ionizing radiation (IR) requires further investigation. This study aimed to characterize how distinct neural lineages present in a developing brain respond to IR, and how these cells repair DNA damage incurred by IR. Cells of the oligodendrocyte lineage, and particularly, oligodendrocyte progenitor cells (OPCs), exhibit marked radiosensitivity relative to other neural cell types, both post-mitotic and replicative. These OPCs are sensitive to a single dose of IR as low as 0.25 Gy, and display impaired DNA double-strand break (DSB) repair kinetics with a high baseline level of accumulated DSBs. While high in reactive oxygen species, modulation of the oxidative stress levels of OPCs is ineffective in rescuing radiosensitivity or DSB levels at rest. Interestingly, OPCs are profoundly sensitive to small molecules that compromise replication fork stability, and have other indicators consistent with aberrant collapsed replication fork processing and repair. Though the reason for this replication phenomenon remains elusive, it may be related to a baseline difficulty engaging HR-directed fork repair and restart mechanisms. Altogether, these data provide cellular mechanisms for the sensitivity of the developing brain to IR. Highly radiosensitive OPCs, more abundant and proliferative in the pediatric brain, might be ablated by IR at a young age. This may contribute in part to the clinical late effects of pediatric cranial radiotherapy. Further understanding of this sensitive cell type might provide an opportunity to protect the developing brain from IR, decrease the severity of late effects of childhood CRT, and provide the safest, most effective treatment for childhood brain cancers.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.DNA damageNeurodevelopmentOligodendrocyteOligodendrocyte progenitor cellsNeural stem cellsRadiation biologyBiology--MolecularNeuroscienceChemistry--Radiationdoctoral thesis10.11575/PRISM/37837