Human tyrosyl-DNA phosphodiesterase 1: new activities and development of enzyme inhibitors as anticancer drugs

Lavrik, O.
December 2015
Biopolymers & Cell;2015 Suppl. 5, p13
Academic Journal
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is responsible to process topoisomerase 1 (TOP1) - DNA adducts as well as to hydrolyze a variety of other DNA 3'-substituents. We have shown recently that TDP1 can initiate repair of apurinic/apyrimidinic (AP) sites located in the internal positions of DNA generating breaks with the 3'- and 5'-phosphate termini [1-3]. This activity was not observed for TDP1 SCAN mutant responsible for neurodegeneration. Polynucleotide kinase phosphatase, Polß and DNA ligase coordinated with XRCC1 are completing repair of the AP sites. The AP site cleaving activity of TDP1 is shown to be stimulated by the key modulator of base excision repair (BER) - poly(ADP-ribose)polymerase 1 (PARP1). The data suggest a role of TDP1 in the new APE1-independent BER pathway in mammals. This activity can contribute to repair of AP sites particularly in ssDNA structures or in the context of cluster-type lesions. The specific real-time fluorescent detection of the AP-site cleaving activity of TDP1 was developed, which is not sensitive to AP site cleavage by APE1 and useful to evaluate a biological significance of new TDP1 function to initiate cleavage of AP sites. TDP1 is a promising target for antitumor therapy based on TOP1 poison-mediated DNA damage. The row of novel benzopentathiepins and other compounds were synthesized and tested as TDP1 inhibitors using an original oligonucleotide-based fluorescence assay [4]. The benzopentathiepines showed IC50 values in the range of 0.2-6.0 µM. The specificity of these inhibitors was investigated by using other target DNA repair proteins such as PARP1, PARP2, AP-endonuclease 1 and DNA polymerase beta. The study of cytotoxicity of these compounds revealed that their action leads to the apoptotic cell death of cancer cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated, which are very prominent to improve cancer therapy based on TOP1 poison-mediated DNA damage.


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