title: Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends.
abstract: Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi, Niigata 951-8122, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tada
authors.forename: Shuichi
authors.initials: S
authors.lastname: Igarashi
authors.forename: Akihide
authors.initials: A
authors.lastname: Koyama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D001072:Apraxias / Q000235:genetics*; D001259:Ataxia / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D006016:Glycolates / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D029867:Xenopus Proteins
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D006016:Glycolates; D009687:Nuclear Proteins; D010710:Phosphates; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D000249:Adenosine Monophosphate; D006157:Guanosine Monophosphate; D004247:DNA; D019951:DNA Polymerase beta; D010744:Phosphoric Monoester Hydrolases; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C013193:phosphoglycolate