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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Spinocerebellar ataxia with axonal neuropathy: Consequence of a Tdp1 recessive neomorphic mutation?
EMBO Journal, Volume 26, No. 22, Year 2007
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Description
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3′ end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1-/- mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1-/- mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant. ©2007 European Molecular Biology Organization.
Authors & Co-Authors
Hirano, Ryuki
Canada, Vancouver
Bc Children's Hospital Research Institute
Canada, Vancouver
The University of British Columbia
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Interthal, Heidrun
United States, Seattle
University of Washington School of Medicine
Huang, Cheng
United States, Houston
Baylor College of Medicine
Nakamura, Tomonori
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Deguchi, Kimiko
United States, Houston
Baylor College of Medicine
Choi, Kunho
Canada, Vancouver
Bc Children's Hospital Research Institute
Canada, Vancouver
The University of British Columbia
Bhattacharjee, Meenakshi Bidwai
United States, Houston
Baylor College of Medicine
Arimura, Kimiyoshi
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Umehara, Fujio
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Izumo, Shuji
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Northrop, Jennifer L.
United States, Houston
Baylor College of Medicine
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
College of Medicine
Inoue, Ken
Japan, Kodaira
National Institute of Neuroscience, Kodaira
Armstrong, Dawna L.
United States, Houston
Baylor College of Medicine
Champoux, James J.
United States, Seattle
University of Washington School of Medicine
Takashima, Hiroshi
Japan, Kagoshima
Kagoshima University Graduate School of Medical and Dental Sciences
Boerkoel, Cornelius F.
Canada, Vancouver
Bc Children's Hospital Research Institute
Canada, Vancouver
The University of British Columbia
Canada, Vancouver
Children's and Women's Health Centre of British Columbia
Statistics
Citations: 35
Authors: 17
Affiliations: 8
Identifiers
Doi:
10.1038/sj.emboj.7601885
ISSN:
02614189
e-ISSN:
14602075
Research Areas
Cancer
Genetics And Genomics