NEIL1
Endonuclease 8-like 1 (EC 3.2.2.-) (EC 4.2.99.18) (DNA glycosylase/AP lyase Neil1) (DNA-(apurinic or apyrimidinic site) lyase Neil1) (Endonuclease VIII-like 1) (FPG1) (Nei homolog 1) (NEH1) (Nei-like protein 1)
Publications[править]
Cellular exposure to ionizing radiation leads to oxidatively generated DNA damage, which has been implicated in neurodegenerative diseases. DNA damage is repaired by the evolutionarily conserved base excision repair (BER) system. Exposure of mice to ionizing radiation affects neurogenesis and neuroinflammation. However, the consequences of deficient DNA repair on adult neurogenesis and neuroinflammation are poorly understood despite their potential relevance for homeostasis. We previously reported that loss of NEIL1, an important DNA glycosylase involved in BER, is associated with deficiencies in spatial memory, olfaction, and protection against ischemic stroke in mice. Here, we show that Neil1 mice display an anxiety-mediated behavior in the open field test, a deficient recognitive memory in novel object recognition and increased neuroinflammatory response under basal conditions. Further, mice lacking NEIL1 have decreased neurogenesis and deficient resolution of neuroinflammation following gamma irradiation (IR)-induced stress compared to WT mice. Neil1 IR-exposed mice also exhibit increased DNA damage and apoptosis in the hippocampus. Interestingly, behavioral tests two weeks after IR showed impaired stress response in the Neil1 mice. Our data indicate that NEIL1 plays an important role in adult neurogenesis and in the resolution of neuroinflammation.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Behavior, Animal
- Cell Proliferation
- Central Nervous System
- DNA Damage
- DNA Glycosylases
- DNA Repair
- Fear
- Gamma Rays
- Gene Expression Profiling
- Hippocampus
- Inflammation
- Male
- Maze Learning
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neural Stem Cells
- Neurodegenerative Diseases
- Oligonucleotide Array Sequence Analysis
- RNA
- Stress, Psychological
Keywords
- DNA damage
- DNA microarray
- NEIL1
- Neurogenesis
- Neuroinflammation
Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans.
MeSH Terms
- Aging
- Animals
- Cell Line
- DNA
- DNA Damage
- DNA Glycosylases
- Gene Knockout Techniques
- Genome
- Genomic Instability
- Homeostasis
- Humans
- Inflammation
- Mice
- Oxidation-Reduction
- RNA Polymerase II
- Telomere
- Transcription, Genetic
Keywords
- DNA damage
- DNA damage and repair
- DNA enzyme
- DNA glycosylase
- NEIL2
- gene knockout
- inflammation
- knock-out animals
- reactive oxygen species
- transcription-coupled repair