DNA single-strand break repair is impaired in aprataxin-related ataxia

Makito Hirano, Aya Yamamoto, Toshio Mori, Li Lan, Taka Aki Iwamoto, Masashi Aoki, Keiji Shimada, Yoshiko Furiya, Shingo Kariya, Hirohide Asai, Akira Yasui, Tomohisa Nishiwaki, Kyoko Imoto, Nobuhiko Kobayashi, Takao Kiriyama, Tetsuya Nagata, Noboru Konishi, Yasuto Itoyama, Satoshi Ueno

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)162-174
Number of pages13
JournalAnnals of Neurology
Issue number2
Publication statusPublished - 2007 Feb

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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