Tyrosyl–DNA phosphodiesterases: rescuing the genome from the risks of relaxation

Abstract

Tyrosyl–DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3′ DNA ends, topoisomerase 2 (Top II)-induced 5′-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase–DNA lesions in the nervous system. TDP1 can promiscuously process several blocked 3′ ends generated by DNA damaging agents and nucleoside analogs in addition to hydrolyzing 3′-phosphotyrosyl residues. In addition, deficiency of these enzymes causes hypersensitivity to anti-tumor topoisomerase poisons. Thus, TDP1 and TDP2 are promising therapeutic targets and their inhibitors are expected to significantly synergize the effects of current anti-tumor therapies including topoisomerase poisons and other DNA damaging agents. This review covers the structural aspects, biology and regulation of these enzymes, along with ongoing developments in the process of discovering safe and effective TDP inhibitors.

Initiation of homologous recombination at DNA nicks

“…SSBs with 5′-AMP termini depend upon aprataxin (APTX) for clean-up (4). Two structurally distinct enzymes, tyrosyl DNA phosphodiesterase 1 (TDP1) and tyrosyl DNA phosphodiesterase 2 (TDP2) cleans up proteolytic fragments of topoisomerases trapped at 3′ and 5′ DNA ends, respectively (8). …”

Complex genetic interactions between DNA polymerase β and the NHEJ ligase

“…4). In this regard, it is interesting to note that Top1 cleavage complexes are the substrates of tyrosyl-DNA phosphodiesterase I (TDP1), an enzyme that catalyzes the removal of covalent 3 0 -DNA adducts [29][30][31]. 4).…”

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

“…Tdp1 participates in repairing stalled DNA–Top1 covalent complexes by catalyzing the hydrolysis of the 3′‐phosphodiester bond between the tyrosine residue of Top1 and DNA 3′‐phosphate following Top1 proteasome degradation . Tdp1 can also repair other anticancer and antiviral drug‐induced damages, such as 3′‐abasic sites, 3′‐phosphoglycolates, and 3′‐nucleoside adducts . Thus, Tdp1 inhibition can increase therapeutic efficiency of these anticancer and antiviral drugs.…”

“…The ability of Tdp1 to cleave different substrates from the 3′‐end of DNA and the fact that Tdp1 expression level affects the sensitivity of tumor cells to anticancer drugs implies that suppressing Tdp1 is a promising strategy for sensitizing tumor cells to the action of Top1 poisons, radiation or radiomimetic drugs, nucleoside analogs, and alkylating agents. The search for Tdp1 inhibitors commenced in 2002 by testing weakly effective nonspecific inhibitors including transition metals, such as vanadate and tungstate; aminoglycoside antibiotics; diamidines, and phosphotyrosine mimetics . Many other synthesized compounds, including naturally occurring plant and fungal metabolites and their derivatives or analogs, have been tested as Tdp1 inhibitors .…”

“…5,15,16 Tdp1 can also repair other anticancer and antiviral drug-induced damages, such as 3′-abasic sites, 3′-phosphoglycolates, and 3′-nucleoside adducts. 5,17,18 Thus, Tdp1 inhibition can increase therapeutic efficiency of these anticancer and antiviral drugs. The mechanism underlying the hydrolysis reaction involves two main catalytic residues, His493 and His263, identified using the structural data [19][20][21][22] (Figure 2).…”