ArticleThe Journal of biological chemistry2012
Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 60 citations in OpenAlex.
- Human topoisomerases and their roles in genome stability and organization.Nature reviews. Molecular cell biology · 2022Review
- New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2.Molecules (Basel, Switzerland) · 2021Article
- The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.Bioorganic chemistry · 2021Article
- Polθ promotes the repair of 5'-DNA-protein crosslinks by microhomology-mediated end-joining.Cell reports · 2021Article
- Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes.Science advances · 2021Article
- Topoisomerase-Mediated DNA Damage in Neurological Disorders.Frontiers in aging neuroscience · 2021Review
- DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks.Cell reports · 2020Article
- Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC).DNA repair · 2020Review
- Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.DNA repair · 2020Article
- Molecular mechanisms of topoisomerase 2 DNA-protein crosslink resolution.Cellular and molecular life sciences : CMLS · 2020Review
- DNA-protein cross-link repair: what do we know now?Cell & bioscience · 2020Review
- Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity.Molecular cell · 2019Article
- Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes.International journal of molecular sciences · 2018Article
- New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2).European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2018Article
- Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2).European journal of medicinal chemistry · 2018Article
- Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2EMBO reports · 2018Article
- Tyrosyl-DNA phosphodiesterases: rescuing the genome from the risks of relaxation.Nucleic acids research · 2018Review
- Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I.Journal of medicinal chemistry · 2017Article
- Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2).Journal of medicinal chemistry · 2017Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
TDP2 is a multifunctional enzyme previously known for its role in signal transduction as TRAF and TNF receptor-associated protein (TTRAP) and ETS1-associated protein 2 (EAPII). The gene has recently been renamed TDP2 because it plays a critical role for the repair of topoisomerase II cleavage complexes (Top2cc) and encodes an enzyme that hydrolyzes 5'-tyrosine-DNA adducts that mimic abortive Top2cc. Here we further elucidate the DNA-processing activities of human recombinant TDP2 and its biochemical characteristics. The preferred substrate for TDP2 is single-stranded DNA or duplex DNA with a four-base pair overhang, which is consistent with the known structure of Top2cc or Top3cc. The k(cat)/K(m) of TDP1 and TDP2 was determined. It was found to be 4 × 10(5) s(-1)M(-1) for TDP2 using single-stranded 5'-tyrosyl-DNA. The processing of substrates as short as five nucleotides long suggests that TDP2 can directly bind DNA ends. 5'-Phosphodiesterase activity requires a phosphotyrosyl linkage and tolerates an extended group attached to the tyrosine. TDP2 requires Mg(2+) or Mn(2+) for efficient catalysis but is weakly active with Ca(2+) or Zn(2+). Titration with Ca(2+) demonstrates a two-metal binding site in TDP2. Sequence alignment suggests that TDP2 contains four conserved catalytic motifs shared by Mg(2+)-dependent endonucleases, such as APE1. Substitutions at each of the four catalytic motifs identified key residues Asn-120, Glu-152, Asp-262, and His-351, whose mutation to alanine significantly reduced or completely abolished enzymatic activity. Our study characterizes the substrate specificity and kinetic parameters of TDP2. In addition, a two-metal catalytic mechanism is proposed.
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