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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo
EMBO Journal, Volume 26, No. 22, Year 2007
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Description
Defective Tyrosyl-DNA phosphodiesterase 1 (TDP1) can cause spinocerebellar ataxia with axonal neuropathy (SCAN1), a neurodegenerative syndrome associated with marked cerebellar atrophy and peripheral neuropathy. Although SCAN1 lymphoblastoid cells show pronounced defects in the repair of chromosomal single-strand breaks (SSBs), it is unknown if this DNA repair activity is important for neurons or for preventing neurodegeneration. Therefore, we generated Tdp1-/- mice to assess the role of Tdp1 in the nervous system. Using both in vitro and in vivo assays, we found that cerebellar neurons or primary astrocytes derived from Tdp1-/- mice display an inability to rapidly repair DNA SSBs associated with Top1-DNA complexes or oxidative damage. Moreover, loss of Tdp1 resulted in age-dependent and progressive cerebellar atrophy. Tdp1-/- mice treated with topotecan, a drug that increases levels of Top1-DNA complexes, also demonstrated significant loss of intestinal and hematopoietic progenitor cells. These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1-associated DNA strand breaks. ©2007 European Molecular Biology Organization.
Authors & Co-Authors
Katyal, Sachin
United States, Memphis
St. Jude Children's Research Hospital
El-Khamisy, Sherif F.
United Kingdom, Brighton
Genome Damage and Stability Centre
Egypt, Cairo
Faculty of Pharmacy - Ain Shams University
Russell, Helen R.
United States, Memphis
St. Jude Children's Research Hospital
Li, Yang
United States, Memphis
St. Jude Children's Research Hospital
Ju, Limei
United Kingdom, Brighton
Genome Damage and Stability Centre
Caldecott, Keith W.
United Kingdom, Brighton
Genome Damage and Stability Centre
McKinnon, Peter J.
United States, Memphis
St. Jude Children's Research Hospital
Statistics
Citations: 189
Authors: 7
Affiliations: 3
Identifiers
Doi:
10.1038/sj.emboj.7601869
ISSN:
02614189
e-ISSN:
14602075
Research Areas
Cancer
Genetics And Genomics