Tyrosyl-DNA phosphodiesterase 1 (TDP1)

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme belonging to the phospholipase D superfamily[4][5]. It catalyzes the hydrolysis of the phosphodiester bond linking a tyrosine residue of topoisomerase I to the 3' phosphate of DNA[1][3][5]. This activity is critical for resolving stalled topoisomerase I-DNA complexes, particularly those trapped by anticancer drugs such as camptothecin. TDP1 also processes various 3'-blocking DNA lesions, contributing to genome stability and cell survival[3][5]. In humans, mutations in the TDP1 gene cause spinocerebellar ataxia with axonal neuropathy (SCAN1), underlining its essential role in neuronal homeostasis[5]. TDP1 has emerged as a potential therapeutic target for cancer, especially to potentiate the effects of topoisomerase I poisons[3]. However, no clinically approved direct TDP1 inhibitors exist; ongoing research is focused on exploiting its role in DNA repair for cancer therapy. Inhibiting TDP1 in normal tissues poses safety concerns, particularly for tissues with high DNA repair requirements or in the nervous system, as indicated by the neurodegenerative consequences of TDP1 mutations[5].

Other names

Tyrosyl-DNA phosphodiesterase 1TDP1Tyr-DNA phosphodiesterase 1FLJ11090SCAN1tyr-DNA phosphodiesterase 1

Inhibition of TDP1 impairs repair of topoisomerase I-DNA complexes, enhancing cytotoxicity of topoisomerase I inhibitors (e.g., camptothecin); supports pro-apoptotic and antiproliferative effects in cancer in combination settings