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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) : from spinocerebellar ataxia to roles in mitochondrial DNA repair and cancer therapy Fam, Hok Khim


Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a 3’-DNA phosphodiesterase that resolves a variety of physiological and drug-induced 3’DNA-blocking lesions. This activity makes Tdp1 an important component of the base-excision repair pathway. While the biochemical activity of Tdp1 has been extensively studied, little is known about its role in cellular homeostasis. Nonetheless, the importance of Tdp1 in humans is exemplified by the observation that its dysfunction and dysregulation is associated with disorders such as neurodegeneration and cancer. My research attempts to broaden our understanding of Tdp1 as a DNA repair protein by providing a cell-physiological context within which the associations to these malignancies may be explored. I begin by characterizing Tdp1 expression in human tissue and exploring the significance of nuclear vs. mitochondrial Tdp1 localization in a subset of tissues. I observed that oxidative stress causes Tdp1 translocation from the nucleus into mitochondria, and identified through the use of human, yeast and mouse models a mechanism by which Tdp1 enters the mitochondria, as well as the mitochondrial DNA damage and respiratory impairment that occurs in the absence of Tdp1. The latter half of my work explores synthetic lethal approaches that may be used to target elevated Tdp1 expression in rhabdomyosarcoma. I found the combination of Tdp1 knockdown and PARP-inhibitor treatment to be effective in attenuating the growth of cultured rhabdomyosarcoma cells. Further validating my findings, I show through the identification of a Tdp1 inhibitor from small molecule libraries that the use of dual Tdp1 and PARP1 inhibition is a potent means of inhibiting the growth of Tdp1-expressing breast cancer cells. Taken together, my studies provide the foundation for further investigation into Tdp1- associated mitochondrial pathologies and the of targeting Tdp1 in cancer therapy.

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