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.DNA damage | formamidopyrimidine-DNA glycosylase/endonuclease VIII | hydantoins | neural stem cells | neuronal progenitor cells T he base-excision repair pathway (BER) maintains genomic integrity by removing base lesions caused by oxidation, alkylation, and deamination. DNA base lesions frequently are cytotoxic or mutagenic if not removed. BER is initiated by DNA glycosylases that recognize modified bases and catalyze cleavage of the N-glycosidic bond, creating an apurinic or apyrimidinic (AP) site. The exposed DNA backbone is cleaved by the AP lyase activity of bifunctional DNA glycosylases or by an AP endonuclease. Repair synthesis is completed by gap filling and ligation (1, 2).Endonuclease VIII-like 3 (NEIL3) and endonuclease VIII-like 1 (NEIL1) are mammalian oxidized base-specific DNA glycosylases (3, 4). The function of NEIL3 has remained enigmatic, but recently the mouse ortholog was shown to remove a broad spectrum of oxidative base lesions on single-stranded DNA substrates with preference for spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh), which are further oxidation products of one of the most common base lesions, 8-oxo-7,8-dihydroguanine (8ohG) (5). These findings suggest that NEIL3 serves as a DNA glycosylase to prevent accumulation of cytotoxic and mutagenic DNA lesions in mammalian cells, although the activity of NEIL1 far exceeds that of NEIL3 on most substrates.In the late postnatal and adult brain, newborn neurons arise from neural stem/progenitor cells (NSPCs) in both the subgranular zone (SGZ) of the hippocampal dentate gyrus and in the subventricular zone (SVZ) (6). We previously reported a discrete expression pattern of Neil3 in the rodent SGZ and SVZ, confined to the embryonic and perinatal stages (7,8). These observations indicate a role for Neil3 in proliferating cells in the brain. However, naïve Neil3-knockout mice generated by us and others (4) appear phenotypically normal. After perinatal hypoxic-ischemic (HI) and adult ischemic stroke, proliferation of SVZ NSPCs is enhanced, and differentiating p...

Accumulation of oxidative DNA damage has been proposed as a potential cause of age-related cognitive decline. The major pathway for removal of oxidative DNA base lesions is base excision repair, which is initiated by DNA glycosylases. In mice, Neil3 is the main DNA glycosylase for repair of hydantoin lesions in single-stranded DNA of neural stem/progenitor cells, promoting neurogenesis. Adult neurogenesis is crucial for maintenance of hippocampus-dependent functions involved in behavior. Herein, behavioral studies reveal learning and memory deficits and reduced anxiety-like behavior in Neil3(-/-) mice. Neural stem/progenitor cells from aged Neil3(-/-) mice show impaired proliferative capacity and reduced DNA repair activity. Furthermore, hippocampal neurons in Neil3(-/-) mice display synaptic irregularities. It appears that Neil3-dependent repair of oxidative DNA damage in neural stem/progenitor cells is required for maintenance of adult neurogenesis to counteract the age-associated deterioration of cognitive performance.

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In this review oxygenation and hyperoxic injury of newborn infants are described through molecular and genetic levels. Protection and repair mechanisms that may be important for a new understanding of oxidative stress in the newborn are discussed. The research summarized in this article represents a basis for the reduced oxygen supplementation and oxidative load of newborn babies, especially since the turn of the century. The mechanisms discussed may also contribute to an understanding of why hyperoxic resuscitation of the newborn may damage DNA and affect its repair, thus increasing the risk that it may be carcinogenic. Today, term babies should be resuscitated with air rather than 100% oxygen and very and extremely low birth weight infants in need of stabilization or resuscitation at birth should be administered initially 21–30% oxygen and the level should be titrated according to the response, preferably measured by pulse oximetry. In the postnatal period the oxygen saturation should be targeted low <95%; however, saturations between 85 and 89% seem to increase mortality. The optimal oxygen saturation target for these infants postnatally is still unknown.