Tyrosyl-DNA phosphodiesterase 2 (TDP2)

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a magnesium/manganese-dependent DNA repair enzyme that catalyzes the hydrolysis of 5'-phosphotyrosyl bonds linking DNA to topoisomerase II (TOP2) or topoisomerase III during abortive reactions, thereby permitting subsequent DNA repair and ligation[1][2][3][5]. TDP2 is essential for removing highly cytotoxic DNA-protein covalent complexes—termed TOP2 cleavage complexes—that block transcription and replication if left unrepaired[1][3]. TDP2 acts predominantly at double-strand breaks but is also co-opted by some RNA viruses (such as picornaviruses) to release their genome from protein primers (VPg unlinkase activity)[1]. Structurally, TDP2 contains an N-terminal ubiquitin-associated domain and a catalytic C-terminal EEP domain with several conserved motifs essential for metal-dependent phosphodiesterase activity, structurally and mechanistically similar to AP endonuclease 1 (APE1)[2][5]. Loss of TDP2 function confers cell hypersensitivity to TOP2 poisons (e.g., etoposide), supporting its role as a therapeutic target for cancer potentiation strategies[3]. No clinically approved drugs target TDP2 specifically, but inhibitors are in development for use in combination with DNA-damaging chemotherapies[1][3].

Other names

TTRAPEAPIIETS1-associated protein 2ETS1-associated protein IITRAF and TNF receptor-associated protein5'-tyrosyl-DNA phosphodiesterase5'-Tyr-DNA phosphodiesteraseTyrosyl-RNA phosphodiesteraseVPg unlinkaseEAP2AD-022hTDP2AD022dJ30M3.3epididymis secretory sperm binding protein

Small molecule inhibitors of TDP2 inhibit the repair of covalent topoisomerase II–DNA complexes, enhancing the cytotoxicity of topoisomerase II poisons. Sensitization to chemotherapeutics that induce topoisomerase II–mediated DNA breaks.