Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

Abstract

TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3′-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5′-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents.

Neuroprotection and repair of 3′-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1)

“…3B). On the contrary, there was no detectable rough eye phenotype in TDP1 adults fed as larvae with etoposide, a Top2 poison (40,41), for which DNA repair is primarily carried out by TDP2 (8,30,42). Our results demonstrate that TDP1 contributes significantly to epithelial cell maintenance in the face of Top1-mediated and oxidative DNA damage.…”

“…Top1 cleavage complexes accumulate at damaged DNA sites (8,35) under normal conditions (22,36), and TDP1 repairs not only Top1-mediated DNA damage but also endogenous oxidative DNA lesions (2,8,12). Both of these types of damage can result in increased mortality, and we therefore tested whether TDP1 influences the lifespan of tdp1Δ flies.…”

“…To ligate and extend the ends of broken DNA, the modified 3′ end must be removed. Tyrosyl-DNA phosphodiesterase (TDP1), first identified in yeast, catalyzes the hydrolysis of 3′-phosphotyrosyl, 3′-phosphoglycolate, and 3′-nucleoside bonds (8,(10)(11)(12)(13)(14). The irreversible Top1-DNA complexes and 3′-blocking nucleoside lesions are cleaved by TDP1, leaving 3′-terminal phosphates, which are further processed by polynucleotide kinase phosphatase before ligation and/or extension by polymerases.…”

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

“…In closing, it is relevant to note that in type IA topoisomerases, the Top3 enzymes also form 5Ј-tyrosyl catalytic intermediates (2,42). Thus, further studies are warranted to determine the potential relevance of TDP2 for the repair of Top3␣⅐DNA and Top3␤⅐DNA or RNA complexes (42)(43)(44)(45).…”

“…6 and 7), which is relevant to the fact that TDP2 is not only associated with the repair of Top2 cleavage complexes (24) but has also been identified as the VPg unlinkase for picornaviruses, a large viral family including poliovirus, coxsackieviruses, rhinoviruses, and the classical foot-and-mouth disease virus (36). In closing, it is relevant to note that in type IA topoisomerases, the Top3 enzymes also form 5Ј-tyrosyl catalytic intermediates (2,42). Thus, further studies are warranted to determine the potential relevance of TDP2 for the repair of Top3␣⅐DNA and Top3␤⅐DNA or RNA complexes (42)(43)(44)(45).…”