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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:
 [1];  [2]; ; ; ;  [1]
  1. Department of Neurology, Faculty of Medicine, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522 (Japan)
  2. Department of Neurology, Faculty of Medicine, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522 (Japan), E-mail: hirano_makto@yahoo.co.jp
Publication Date:
OSTI Identifier:
21143884
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 374; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2008.07.088; PII: S0006-291X(08)01392-2; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; DISEASES; DNA; DNA REPAIR; FIBROBLASTS; LIGASES; MUTANTS; NERVE CELLS; OXIDATION; PATHOGENESIS; PATIENTS; STRESSES

Citation Formats

Kiriyama, Takao, Hirano, Makito, Asai, Hirohide, Ikeda, Masanori, Furiya, Yoshiko, and Ueno, Satoshi. Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.07.088.
Kiriyama, Takao, Hirano, Makito, Asai, Hirohide, Ikeda, Masanori, Furiya, Yoshiko, & Ueno, Satoshi. Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. United States. doi:10.1016/j.bbrc.2008.07.088.
Kiriyama, Takao, Hirano, Makito, Asai, Hirohide, Ikeda, Masanori, Furiya, Yoshiko, and Ueno, Satoshi. 2008. "Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress". United States. doi:10.1016/j.bbrc.2008.07.088.
@article{osti_21143884,
title = {Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress},
author = {Kiriyama, Takao and Hirano, Makito and Asai, Hirohide and Ikeda, Masanori and Furiya, Yoshiko and Ueno, Satoshi},
abstractNote = {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.},
doi = {10.1016/j.bbrc.2008.07.088},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 374,
place = {United States},
year = 2008,
month =
}
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