Tyrosyl-DNA Phosphodiesterase 1 as a Target for Anticancer Therapy

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) was initially discovered as an enzyme that catalyzes the hydrolysis of 3’-phosphotyrosyl bonds. Such linkages are transiently introduced in vivo by the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1- DNA covalent complexes (Top1cc), which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1-targeting drugs. Tdp1 inhibitors may also selectively target cancer cells with defects in alternative repair pathways for Top1cc, e.g. DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3’-end DNA alterations including 3’-phosphoglycolates and 3’-abasic sites indicating it may function as a general 3’-end processing repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human Tdp1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

Keywords: Tyrosyl-DNA phosphodiesterase, topoisomerase, DNA repair, PARP, proteasome, PNK, camptothecin, indenoisoquinoline.