Abstract
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that processes blocked 3′ ends of DNA breaks. Functional loss of Tdp1 causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Based on the prominent cytoplasmic expression of Tdp1 in the neurons presumably affected in SCAN1, we hypothesized that Tdp1 participates in the repair of mitochondrial DNA. As a step toward testing this hypothesis, we profiled Tdp1 expression in different human tissues by immunohistochemistry and immunofluorescence respectively and determined whether Tdp1 was expressed in the cytoplasm of tissues other than the neurons. We found that Tdp1 was ubiquitously expressed and present in the cytoplasm of many cell types. Within human skeletal muscle and multiple mouse tissues, Tdp1 partially colocalized with the mitochondria. In cultured human dermal fibroblasts, Tdp1 redistributed to the cytoplasm and partially colocalized with mitochondria following oxidative stress. These studies suggest that one role of cytoplasmic Tdp1 is the repair of mitochondrial DNA lesions arising from oxidative stress.
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Acknowledgments
The authors thank Dr. Alireza Baradaran-Heravi and Marie Morimoto for their criticism, suggestions and review of this manuscript. This work was supported in part by a United Mitochondrial Disease Foundation Award (C.F.B.), a Child & Family Research Institute Establishment Award (C.F.B.) and a Canadian Institutes of Health Research Award (248178, C.F.B.). M.K.C. was supported by a Michael Cuccione Studentship for Oncology Research. C.F.B. is a scholar of the Michael Smith Foundation for Health Research and a Clinical Investigator of the Child & Family Research Institute.
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Hok Khim Fam, Miraj K. Chowdhury and Cheryl Walton have contributed equally to this work.
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Fam, H.K., Chowdhury, M.K., Walton, C. et al. Expression profile and mitochondrial colocalization of Tdp1 in peripheral human tissues. J Mol Hist 44, 481–494 (2013). https://doi.org/10.1007/s10735-013-9496-5
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DOI: https://doi.org/10.1007/s10735-013-9496-5