title: Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein.
abstract: Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early-onset ataxia, ocular motor apraxia, and hypoalbuminemia. Recently, the causative gene for EAOH, APTX, has been identified. Of the two splicing variants of APTX mRNA, the short and the long forms, long-form APTX mRNA was found to be the major isoform. Aprataxin is mainly located in the nucleus, and, furthermore, the first nuclear localization signal located near the amino terminus of the long-form aprataxin is essential for its nuclear localization. We found, based on the yeast two-hybrid and coimmunoprecipitation experiments, that the long-form but not the short-form aprataxin interacts with XRCC1 (x-ray repair cross-complementing group 1). Interestingly the amino terminus of the long-form aprataxin is homologous with polynucleotidekinase-3'-phosphatase, which has been demonstrated to be involved in base excision repair, a subtype of single-strand DNA break repair, through interaction with XRCC1, DNA polymerase beta, and DNA ligase III. These results strongly support the possibility that aprataxin and XRCC1 constitute a multiprotein complex and are involved in single-strand DNA break repair, and furthermore, that accumulation of unrepaired damaged DNA underlies the pathophysiological mechanisms of EAOH.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Sano
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Shuichi
authors.initials: S
authors.lastname: Igarashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Oyake
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hayashi
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Morimatsu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Takao
authors.initials: T
authors.lastname: Makifuchi
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Fukuhara
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001072:Apraxias / Q000235:genetics*; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D034141:Hypoalbuminemia / Q000235:genetics*; D007150:Immunohistochemistry; D019913:Nuclear Localization Signals / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human