ArticleNucleic acids research2008
A single mutation in the 729 residue modulates human DNA topoisomerase IB DNA binding and drug resistance.
Article in Nucleic acids research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 31 citations in OpenAlex.
- Mutations and Recombination at G4 DNA-Forming Sequences Exacerbated by CPT-Resistant Mutant Topoisomerase 1 Is Dependent on SUMOylation.International journal of molecular sciences · 2025Article
- DNA repair and the contribution to chemotherapy resistance.Genome medicine · 2025Review
- Integrative analysis of multi-omics data reveals inhibition of RB1 signaling promotes apatinib resistance of hepatocellular carcinoma.International journal of biological sciences · 2023Article
- Cleavage-defective Topoisomerase I mutants sharply increase G-quadruplex-associated genomic instability.Microbial cell (Graz, Austria) · 2022Article
- The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA.Genes · 2020Review
- Topoisomerase IB: a relaxing enzyme for stressed DNA.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistance-associated mutations.Journal of experimental & clinical cancer research : CR · 2016Article
- Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.Nucleic acids research · 2013Article
- Molecular mechanism of the camptothecin resistance of Glu710Gly topoisomerase IB mutant analyzed in vitro and in silico.Molecular cancer · 2013Article
- Solvent dependency of the UV-Vis spectrum of indenoisoquinolines: role of keto-oxygens as polarity interaction probes.PloS one · 2013Article
- Characterization of DNA topoisomerase-1 in Spodoptera exigua for toxicity evaluation of camptothecin and hydoxy-camptothecin.PloS one · 2013Article
- Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant.PloS one · 2013Article
- New Topoisomerase I mutations are associated with resistance to camptothecin.Molecular cancer · 2011Article
- Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma.Cancer research · 2011Article
- Evidence of the crucial role of the linker domain on the catalytic activity of human topoisomerase I by experimental and simulative characterization of the Lys681Ala mutant.Nucleic acids research · 2009Article
- Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.Nucleic acids research · 2008Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human DNA topoisomerase I (hTop1p) catalyzes the relaxation of supercoiled DNA and constitutes the cellular target of the antitumor drug camptothecin (CPT). The X-ray crystal structure of the enzyme covalently joined to DNA and bound to the CPT analog Topotecan suggests that there are two classes of mutations that can produce a CPT-resistant enzyme. The first class includes changes in residues that directly interact with the drug, whereas a second class alters interactions with the DNA and thereby destabilizes the drug binding site. The Thr729Ala, that is part of a hydrophobic pocket in the enzyme C-terminal domain, belongs to a third group of mutations that confer CPT resistance, but do not interact directly with the drug or the DNA. To understand the contribution of this residue in drug resistance, we have studied the effect on hTop1p catalysis and CPT sensitivity of four different substitutions in the Thr729 position (Thr729Ala, Thr729Glu, Thr729Lys and Thr729Pro). Tht729Glu and Thr729Lys mutants show severe CPT resistance and furthermore, Thr729Glu shows a remarkable defect in DNA binding. We postulate that the maintenance of the hydrophobic pocket integrity, where Thr729 is positioned, is crucial for drug sensitivity and DNA binding.
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