TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo

Katyal, Sachin, El-Khamisy, Sherif F, Russell, Helen R, Liu, Yang, Ju, Limei, Caldecott, Keith W and McKinnon, Peter J (2007) TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO Journal, 26. pp. 4720-4731. ISSN 0261-4189

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Abstract

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.

Item Type: Article
Additional Information: I am co-correspondng author on this manuscript and my postdoc (El Khamisy) was co-first author.
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Sherif El-Khamisy
Date Deposited: 06 Feb 2012 20:57
Last Modified: 14 Jun 2012 08:30
URI: http://srodev.sussex.ac.uk/id/eprint/28833
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