Annals of neurology · 2007
DNA single-strand break repair is impaired in aprataxin-related ataxia.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Hirano Makito, Yamamoto Aya, Mori Toshio, Lan Li, Iwamoto Taka-aki, Aoki Masashi, Shimada Keiji, Furiya Yoshiko, Kariya Shingo, Asai Hirohide, Yasui Akira, Nishiwaki Tomohisa, Imoto Kyoko, Kobayashi Nobuhiko, Kiriyama Takao, Nagata Tetsuya, Konishi Noboru, Itoyama Yasuto, Ueno Satoshi
Аннотация
OBJECTIVE: Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive form of cerebellar ataxia. The causative protein for EAOH/AOA1, aprataxin (APTX), interacts with X-ray repair cross-complementing 1 (XRCC1), a scaffold DNA repair protein for single-strand breaks (SSBs). The goal of this study was to prove the functional involvement of APTX in SSB repair (SSBR).
METHODS: We visualized the SSBR process with a recently developed laser irradiation system that allows real-time observation of SSBR proteins and with a local ultraviolet-irradiation system using a XPA-UVDE cell line that repairs DNA lesions exclusively via SSBR. APTX was knocked down using small interference RNA in the cells. Oxidative stress-induced DNA damage and cell death were assessed in EAOH fibroblasts and cerebellum.
RESULTS: Our systems showed the XRCC1-dependent recruitment of APTX to SSBs. SSBR was impaired in APTX-knocked-down cells. Oxidative stress in EAOH fibroblasts readily induced SSBs and cell death, which were blocked by antioxidants. Accumulated oxidative DNA damage was confirmed in EAOH cerebellum.
INTERPRETATION: This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.
METHODS: We visualized the SSBR process with a recently developed laser irradiation system that allows real-time observation of SSBR proteins and with a local ultraviolet-irradiation system using a XPA-UVDE cell line that repairs DNA lesions exclusively via SSBR. APTX was knocked down using small interference RNA in the cells. Oxidative stress-induced DNA damage and cell death were assessed in EAOH fibroblasts and cerebellum.
RESULTS: Our systems showed the XRCC1-dependent recruitment of APTX to SSBs. SSBR was impaired in APTX-knocked-down cells. Oxidative stress in EAOH fibroblasts readily induced SSBs and cell death, which were blocked by antioxidants. Accumulated oxidative DNA damage was confirmed in EAOH cerebellum.
INTERPRETATION: This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.
Предметные рубрики MeSH
AdultAnimalsAntibodies, MonoclonalCell DeathCells, CulturedCerebellar AtaxiaCerebellumDNA Breaks, Single-StrandedDNA RepairDNA-Binding ProteinsDrug InteractionsDrug StabilityFemaleFibroblastsGenes, RecessiveHumansLasersMaleMutationNuclear ProteinsOxidative StressProliferating Cell Nuclear AntigenProteasome Endopeptidase ComplexRNA, Small InterferingUltraviolet RaysX-ray Repair Cross Complementing Protein 1