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First published on April 17, 2006; DOI: 10.1124/mol.105.021865

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Received for publication December 19, 2005.
Revised April 15, 2006.
Accepted for publication April 17, 2006.

Inhibition of human Tyrosyl-DNA Phosphodiesterase (Tdp1) by aminoglycoside antibiotics and ribosome inhibitors

Zhiyong Liao 1, Laurent Thibaut 1, Andrew Jobson 1, Yves Pommier 1*

1 NIH

* Address correspondence to: E-mail: pommier{at}nih.gov

Abstract

DNA topoisomerase I (Top1) is the target of camptothecin and novel Top1 inhibitors are in development as anticancer agents. Top1 inhibitors damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3'-end of the broken DNA. Tyrosyl-DNA phosphodiesterase (Tdp1) can repair Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. Inhibiting Tdp1 has the potential to enhance the anticancer activity of Top1 inhibitors (http://discover.nci.nih.gov/pommier/pommier.htm) and to act as antiproliferative agents. In the present study, we report that neomycin inhibits Tdp1 more effectively than the related aminoglycosides paromomycin and lividomycin A. Inhibition of Tdp1 by neomycin is observed both with single- and double-stranded substrates but is slightly stronger with duplex DNA, which is different from aclarubcin, which only inhibits Tdp1 with the single-stranded substrate. Inhibition by neomycin can be overcome with excess Tdp1 and is greatest at low pH. To our knowledge, aminoglycoside antibiotics and the ribosome inhibitors thiostrepton, clindamycin-2-phosphate and puromycin are the first reported pharmacological Tdp1 inhibitors.


Key words: DNA binding sites, Structure-activity relationships and modeling, DNA damage and repair, Protein synthesis inhibitors, Topoisomerases


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