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DNA single‐strand break repair is impaired in aprataxin‐related ataxia
Author(s) -
Hirano Makito,
Yamamoto Aya,
Mori Toshio,
Lan Li,
Iwamoto TakaAki,
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
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21078
Subject(s) - xrcc1 , dna damage , ataxia , oxidative stress , dna repair , chemistry , dna , microbiology and biotechnology , biology , gene , biochemistry , neuroscience , genotype , single nucleotide polymorphism
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. Ann Neurol 2007;61:162–174