Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts

Abstract

Our genomic DNA is under constant assault from endogenous and exogenous sources, which needs to be resolved to maintain cellular homeostasis. The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts. These DNA-adducts can be divided into two groups: small adducts, including oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as (drug-stabilized) topoisomerase-DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA. Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance, making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents. Tdp1's unique catalytic cycle, which is centered on the formation of Tdp1-DNA covalent reaction intermediate, allows for two principally different targeting strategies: (1) catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics; and (2) poisoning of Tdp1 by stabilization of the Tdp1-DNA covalent reaction intermediate, which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution, analogous to topoisomerase targeted poisons such as topotecan or etoposide. The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept; however, no small molecules have been reported for this strategy. Herein, we concisely discuss the development of Tdp1 catalytic inhibitors and their results.

Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells

“…The 3'-cleavage activity of TDP1 has been shown to be involved in the removal of DNA damage induced by CPT and its derivatives, several nucleoside analogs and alkylating agents [36-38, 40, 41]. Consistent with previous findings [38,[40][41][42][43], tdp1 DT40 cells were also sensitive to VP16 (Fig 1B). These results confirm the known cellular phenotypes of tdp1-and tdp2-deficient cells.…”

“…The mechanism of TDP1-mediated repair of DPCs induced by formaldehyde is unclear. TDP1 acts on the 3'-blocked end at a strand break and removes the 3'-blocked end by 3'-cleavage activity [36][37][38]. Thus, a 3'-end proximal to DPC may be required for the DPC repair activity of TDP1.…”

“…Thus, tdp1-and tdp2-deficient cells display hypersensitivity to CPT or VP16, respectively [35]. Increasing evidence demonstrates that TDP1 has the capacity to remove a broad range of 3'end blocking DNA lesions (3'-cleavage activity) [36][37][38][39]. Recent studies also reported that tdp1-deficient cells were sensitive to VP16 that trapped TOPO2-DNA reaction intermediates [38][39][40][41][42][43].…”

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

“…Since Tdp1 is involved in the removal of DNA damage caused by Top1 poisons, the activity of Tdp1 can lead to the development of drug resistance [ 36 ]. Thus, it is believed that Tdp1 inhibition can enhance the efficacy of Top1 poisons [ 37 ]. Tdp1 inhibitors should have the lowest possible intrinsic toxicity to minimize potential side effects.…”

Inhibition of Tyrosyl-DNA Phosphodiesterase 1 by Lipophilic Pyrimidine Nucleosides

“…DNA repair systems are resistant to the action of chemotherapeutic drugs and ionizing radiation, and therefore the beneficial effect of antitumor therapy depends on the effectiveness of DNA repair systems in tumor cells. Accordingly, targeted inhibition of DNA repair enzymes can increase the effectiveness of chemotherapeutic drugs used in clinical practice and may enable reducing their dose, which in turn can decrease the overall toxicity of treatment [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. A number of enzymes and protein factors are involved in DNA repair [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”