Expression patterns of Neil3 during embryonic brain development and neoplasia

Hildrestrand, Gunn A.; Neurauter, Christine G.; Diep, Dzung B.; Castellanos, Cesilie Granum; Krauß, Stefan; Bjørås, Magnar; Luna, Luisa

doi:10.1186/1471-2202-10-45

Cited by 75 publications

(85 citation statements)

References 38 publications

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“…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.…”

mentioning

confidence: 80%

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

Sejersted¹,

Hildrestrand²,

Kunke³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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127

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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.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...

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mentioning

confidence: 80%

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

Sejersted¹,

Hildrestrand²,

Kunke³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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127

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“…In addition, our finding that MmuNeil3 also recognizes lethal lesions such as Tg and mutagenic lesions such as FapyG, 5-OHU, and 5-OHC, together with the fact that Neil3 is expressed principally in hematopoietic tissues, in tissues that harbor stem cells in the brain, in various tumor tissues, and during embryonic development (17,18,(40)(41)(42) suggests that Neil3 function might be required in proliferating cells to remove lethal and mutagenic lesions from the genome.…”

Section: Mmuneil3mentioning

confidence: 96%

The mouse ortholog of NEIL3 is a functional DNA glycosylase in vitro and in vivo

Liu

Bandaru

Bond

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

176

249

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To protect cells from oxidative DNA damage and mutagenesis, organisms possess multiple glycosylases to recognize the damaged bases and to initiate the Base Excision Repair pathway. Three DNA glycosylases have been identified in mammals that are homologous to the Escherichia coli Fpg and Nei proteins, Neil1, Neil2, and Neil3. Neil1 and Neil2 in human and mouse have been well characterized while the properties of the Neil3 protein remain to be elucidated. In this study, we report the characterization of Mus musculus (house mouse) Neil3 (MmuNeil3) as an active DNA glycosylase both in vitro and in vivo. In duplex DNA, MmuNeil3 recognizes the oxidized purines, spiroiminodihydantoin (Sp), guanidinohydantoin (Gh), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA), but not 8-oxo-7,8-dihydroguanine (8-oxoG). Interestingly, MmuNeil3 prefers lesions in single-stranded DNA and in bubble structures. In contrast to other members of the family that use the N-terminal proline as the nucleophile, MmuNeil3 forms a Schiff base intermediate via its N-terminal valine. We expressed the glycosylase domain of MmuNeil3 (MmuNeil3Δ324) in an Escherichia coli triple mutant lacking Fpg, Nei, and MutY glycosylase activities and showed that MmuNeil3 greatly reduced both the spontaneous mutation frequency and the level of FapyG in the DNA, suggesting that Neil3 plays a role in repairing FapyG in vivo.base excision repair | endonuclease VIII Like 3 | 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) | Spiroiminodihydantoin D NA glycosylases play an important role in maintaining genomic integrity by recognizing various nonhelix distorting base lesions created by ionizing radiation, alkylating, or oxidizing agents, which are often cytotoxic or mutagenic (1). DNA glycosylases cleave the N-glycosylic bond and release the base lesion from the sugar backbone, resulting in an apurinic or apyrimidinic (AP) site (2). Besides glycosylase activity, some of these enzymes also have a lyase activity to process the AP site. In this way, DNA glycosylases initiate the Base Excision Repair (BER) † pathway and create the substrates for further processing by a series of BER enzymes including phosphodiesterases, AP endonucleases, DNA polymerases, and DNA ligases to complete lesion repair (3).DNA glycosylases that recognize oxidized bases can be divided into two families based on structure and sequence homology (4, 5), the Nth family, whose members are widely distributed in bacteria, archaea, and eukaryotes (5), and the Fpg/Nei family, which is more sparsely distributed across phyla. Fpg/Nei family members are characterized by a signature helix-two turns-helix (H2TH) motif and a zinc finger (or "zincless finger") motif for DNA binding; they also have a conserved N terminus harboring a proline residue (P2) important for catalysis (6). In Escherichia coli, formamidopyrimidine DNA glycosylase (EcoFpg) mainly recognizes oxidized purines (7), and endonuclease VIII (EcoNei) mainly recognizes oxidized pyrimidines and adenin...

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“…and NEIL1 (Nei-like DNA glycosylase 1) 68 . Some repair ability has been reported also for NEIL3 69,70 , which is otherwise suggested to be more important for neurogenesis than for classical DNA repair [71][72][73][74] . The mechanisms for regulation of base excision repair after neuronal injury are not well understood.…”

Section: Energy Failure Calcium Overload and Excitotoxicitymentioning

confidence: 99%

Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation

et al. 2009

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Expression patterns of Neil3 during embryonic brain development and neoplasia

Cited by 75 publications

References 38 publications

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

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

The mouse ortholog of NEIL3 is a functional DNA glycosylase in vitro and in vivo

Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation

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