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DNA single-strand break repair is impaired in aprataxin-related ataxia.
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.
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Related Subject Headings
- X-ray Repair Cross Complementing Protein 1
- Ultraviolet Rays
- RNA, Small Interfering
- Proteasome Endopeptidase Complex
- Proliferating Cell Nuclear Antigen
- Oxidative Stress
- Nuclear Proteins
- Neurology & Neurosurgery
- Mutation
- Male
Citation
![Journal cover image](https://secure.syndetics.com/index.aspx?isbn=/lc.gif&issn=0364-5134&client=dukeuniv)
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- X-ray Repair Cross Complementing Protein 1
- Ultraviolet Rays
- RNA, Small Interfering
- Proteasome Endopeptidase Complex
- Proliferating Cell Nuclear Antigen
- Oxidative Stress
- Nuclear Proteins
- Neurology & Neurosurgery
- Mutation
- Male