Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 46, Pages 18802-18807Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1106880108
Keywords
DNA damage; formamidopyrimidine-DNA glycosylase/endonuclease VIII; hydantoins; neural stem cells; neuronal progenitor cells
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Funding
- Research Council of Norway
- Norwegian Cancer Society (Ragnvarda F. Soervik and Haakon Starheim's Foundation)
- The Laerdal Foundation for Acute Medicine
- National Institutes of Health [CA090689]
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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.
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