Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia

Neural stem/progenitor cell proliferation and differentiation are required to replace damaged neurons and regain brain function after hypoxic-ischemic events. DNA base lesions accumulating during hypoxic-ischemic stress are removed by DNA glycosylases in the base-excision repair pathway to prevent c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (46), p.18802-18807
Main Authors: Sejersted, Yngve, Hildrestrand, Gunn A, Kunke, David, Rolseth, Veslemøy, Krokeide, Silje Z, Neurauter, Christine G, Suganthan, Rajikala, Atneosen-Åsegg, Monica, Fleming, Aaron M, Saugstad, Ola D, Burrows, Cynthia J, Luna, Luisa, Bjørås, Magnar
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Brain
Brain hypoxia
Cell Differentiation
Cell Proliferation
Cerebral hemispheres
Cytotoxicity
Differentiation
DNA Damage
DNA glycosylase
DNA repair
DNA, Single-Stranded
Embryos
Endodeoxyribonucleases - genetics
Endodeoxyribonucleases - metabolism
Endonuclease
glycosylases
Hydantoins - metabolism
Hypoxia
Hypoxia - genetics
Ischemia
Ischemia - genetics
Lesions
Mice
Mice, Knockout
Microglia
Mitosis
Multipotent stem cells
Mutagenesis
Neostriatum
Neural stem cells
Neural Stem Cells - cytology
Neurogenesis
Neurons
Neuropathology
Neuroscience
Physical training
Progenitor cells
Rodents
single-stranded DNA
Stem cells
Stem Cells - cytology
Stress
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Summary:Neural stem/progenitor cell proliferation and differentiation are required to replace damaged neurons and regain brain function after hypoxic-ischemic events. DNA base lesions accumulating during hypoxic-ischemic stress are removed by DNA glycosylases in the base-excision repair pathway to prevent cytotoxicity and mutagenesis. Expression of the DNA glycosylase endonuclease VIII-like 3 (Neil3) is confined to regenerative subregions in the embryonic and perinatal brains. Here we show profound neuropathology in Neil3-knockout mice characterized by a reduced number of microglia and loss of proliferating neuronal progenitors in the striatum after hypoxia-ischemia. In vitro expansion of Neil3-deficient neural stem/progenitor cells revealed an inability to augment neurogenesis and a reduced capacity to repair for oxidative base lesions in single-stranded DNA. We propose that Neil3 exercises a highly specialized function through accurate molecular repair of DNA in rapidly proliferating cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1106880108