title: DNA single-strand break repair is impaired in aprataxin-related ataxia.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Radioisotope Research Center, Nara Medical University, Nara, Japan. hirano_makito@yahoo.co.jp
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Mori
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Iwamoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furiya
authors.forename: Shingo
authors.initials: S
authors.lastname: Kariya
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nishiwaki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imoto
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Takao
authors.initials: T
authors.lastname: Kiriyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nagata
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Itoyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueno
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal; D016923:Cell Death; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002531:Cerebellum / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004347:Drug Interactions; D004355:Drug Stability; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005808:Genes, Recessive; D006801:Humans; D007834:Lasers; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014466:Ultraviolet Rays; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C438188:APTX protein, human; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D046988:Proteasome Endopeptidase Complex