title: Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress.
abstract: Triple A syndrome is an autosomal recessive neurological disease, mimicking motor neuron disease, and is caused by mutant ALADIN, a nuclear-pore complex component. We recently discovered that the pathogenesis involved impaired nuclear import of DNA repair proteins, including DNA ligase I and the cerebellar ataxia causative protein aprataxin. Such impairment was overcome by fusing classical nuclear localization signal (NLS) and 137-aa downstream sequence of XRCC1, designated stretched NLS (stNLS). We report here that the minimum essential sequence of stNLS (mstNLS) is residues 239-276, downsized by more than 100 aa. mstNLS enabled efficient nuclear import of DNA repair proteins in patient fibroblasts, functioned under oxidative stress, and reduced oxidative-stress-induced cell death, more effectively than stNLS. The stress-tolerability of mstNLS was also exerted in control fibroblasts and neuroblastoma cells. These findings may help develop treatments for currently intractable triple A syndrome and other oxidative-stress-related neurological diseases, and contribute to nuclear compartmentalization study.
authors.affiliation: Department of Neurology, Faculty of Medicine, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kiriyama
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furiya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueno
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000309:Adrenal Insufficiency / Q000378:metabolism* / Q000628:therapy; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015352:Dry Eye Syndromes / Q000378:metabolism* / Q000628:therapy; D004931:Esophageal Achalasia / Q000378:metabolism* / Q000628:therapy; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D013577:Syndrome; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; C000607892:LIG1 protein, human; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP