TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo |
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Authors: | Katyal Sachin el-Khamisy Sherif F Russell Helen R Li Yang Ju Limei Caldecott Keith W McKinnon Peter J |
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Institution: | Department Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. |
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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. |
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Keywords: | DNA repair neurodegeneration single-strand breaks TDP1 topoisomerase 1 |
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