Mutations of human DNA topoisomerase I at poly(ADP-ribose) binding sites: modulation of camptothecin activity by ADP-ribose polymers

Journal of Experimental & Clinical Cancer Research

Alessandro Desideri¹  Paola Fiorani⁴  Carlo Leonetti²  Lucio Tentori³  Elettra Santori¹  Ilda D¿Annessa¹  Alessia Muzi³  Laura Zuccaro¹  Barbara Arnò¹  Grazia Graziani³  Cinzia Tesauro¹ 

[1] Department of Biology and Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome `Tor Vergata¿, Via della Ricerca Scientifica, Rome 00133, Italy;Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Via delle Messi d¿Oro 156, Rome 00158, Italy;Department of Systems Medicine, University of Rome Tor `Vergata Via¿ Montpellier 1, Rome 00133, Italy;Institute of Translational Pharmacology, National Research Council, CNR, Via del Fosso del Cavaliere 100, Rome 00133, Italy

关键词: PARP inhibitors;    Camptothecin;    Religation rate;    Cleavage;    PARylation;    Topoisomerase I;   

Others  :  1145587
DOI  :  10.1186/s13046-014-0071-z

 received in 2014-07-17, accepted in 2014-08-19,  发布年份 2014

【 摘 要 】

Background

DNA topoisomerases are key enzymes that modulate the topological state of DNA through the breaking and rejoining of DNA strands. Human topoisomerase I belongs to the family of poly(ADP-ribose)-binding proteins and is the target of camptothecin derived anticancer drugs. Poly(ADP-ribosyl)ation occurs at specific sites of the enzyme inhibiting the cleavage and enhancing the religation steps during the catalytic cycle. Thus, ADP-ribose polymers antagonize the activity of topoisomerase I poisons, whereas PARP inhibitors increase their antitumor effects.

Methods

Using site-directed mutagenesis we have analyzed the interaction of human topoisomerase I and poly(ADP-ribose) through enzymatic activity and binding procedures.

Results

Mutations of the human topoisomerase I hydrophobic or charged residues, located on the putative polymer binding sites, are not sufficient to abolish or reduce the binding of the poly(ADP-ribose) to the protein. These results suggest either the presence of additional binding sites or that the mutations are not enough perturbative to destroy the poly(ADP-ribose) interaction, although in one mutant they fully abolish the enzyme activity.

Conclusions

It can be concluded that mutations at the hydrophobic or charged residues of the putative polymer binding sites do not interfere with the ability of poly(ADP-ribose) to antagonize the antitumor activity of topoisomerase I poisons.

【 授权许可】

   
2014 Tesauro et al.; licensee BioMed Central Ltd.

【 图 表 】

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